WO2003047585A1 - Pharmaceutical compositions comprising benzofuranyl substituted 3-cyanoquinoline derivatives and their use for the treatment of solid tumours - Google Patents

Pharmaceutical compositions comprising benzofuranyl substituted 3-cyanoquinoline derivatives and their use for the treatment of solid tumours Download PDF

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Publication number
WO2003047585A1
WO2003047585A1 PCT/GB2002/005536 GB0205536W WO03047585A1 WO 2003047585 A1 WO2003047585 A1 WO 2003047585A1 GB 0205536 W GB0205536 W GB 0205536W WO 03047585 A1 WO03047585 A1 WO 03047585A1
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alkyl
group
ethoxy
propoxy
formula
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PCT/GB2002/005536
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French (fr)
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Laurent Francois Andre Hennequin
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to AU2002347360A priority Critical patent/AU2002347360A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention concerns a new use of novel quinoline derivatives, or pharmaceutically-acceptable salts thereof, which have been found to possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body.
  • Cancer is a disease in which cells grow and divide in an uncontrolled fashion. This uncontrolled growth arises from abnormalities in signal transduction pathways that are used by normal cells to regulate cell growth and division in response to various signalling molecules. Normal cells do not proliferate unless stimulated to do so by specific signal molecules located outside the cell derived from nearby cells or tissues. Growth factors bind to the cell membrane via specific receptors which have intrinsic enzyme activity. These receptors relay the growth signal to the cell nucleus via a series of signalling proteins, hi cancer, a number of defects in signal pathways are apparent.
  • cancer cells may produce their own growth factors which bind to their cognate receptors, resulting in an autocrine loop, or receptors may be mutated or overexpressed leading to an increased, continuous signal to proliferate.
  • negative regulators of cell growth may be lost.
  • Oncogenes are cancer related genes which often encode abnormal versions of signal pathway components, such as receptor tyrosine kinases, serine-threonine kinases, or downstream signaling molecules such as the ras genes, which code for closely related small guanine nucleotide binding proteins which hydrolyse bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP).
  • Ras proteins are active in promoting cell growth and transformation when they are bound to GTP and inactive when they are bound to GDP. Transforming mutants of p2 Iras are defective in their GTPase activity and hence remain in the active GTP bound state.
  • the ras oncogene is known to play an integral role in certain cancers, and has been found to contribute to the formation of over 20% of all cases of human cancer.
  • cell surface receptors which are coupled to the mitogenic response, such as growth factor receptors, initiate a chain of reactions which leads to the activation of guanine nucleotide exchange activity on ras.
  • raf When in its active GTP-bound state, a number of proteins interact directly with ras at the plasma membrane resulting in signal transmission through several distinct pathways.
  • the best characterised effector protein is the product of the raf proto-oncogene.
  • the interaction of raf and ras is a key regulatory step in the control of cell proliferation.
  • Ras-mediated activation of the raf serine-threonine kinase in turn activates the dual-specificity MEK (MEK1 and MEK2), which is the immediate upstream activator of mitogen activated protein kinase (MAPKs known as extracellular signal regulated protein kinases or ERK1 and ERK2).
  • MEK may also be activated by other upstream signal proteins such as MEKKl and Cot/Tpl-2.
  • Activated MAPK translocates and accumulates in the nucleus, where it can phosphorylate and activate transcription factors such as Elk-1 and Sapla, leading to the enhanced expression of genes such as that for c-fos.
  • the ras-dependent raf-MEK-MAPK cascade is one of the key signalling pathways responsible for transmitting and amplifying mitogenic signals from cell surface to the nucleus resulting in changes in gene expression and cell fate. This ubiquitous pathway appears essential for normal cell proliferation and constitutive activation of this pathway is sufficient to induce cellular transformation. Transforming mutants of p21ras are constitutively active, resulting in raf, MEK and MAPK activity and cell transformation. Inhibition of MEK activity using either antisense raf, a dominant negative MEK mutant or the selective inhibitor PD098059 have been shown to block the growth and morphological transformation of ras-transformed fibroblasts.
  • the mechanism of activation of raf, MEK and MAPK is through phosphorylation on specific serine, threonine or tyrosine residues.
  • Activated raf and other kinases phosphorylate MEK1 on S218 and S222 and MEK2 on S222 and S226. This results in MEK activation and subsequent phosphorylation and activation of ERK1 on T190 and Y192 and ERK2 on T183 and Yl 85 by the dual specificity MEKs.
  • MEK can be activated by a number of protein kinases, and active MAPKs phosphorylate and activate a number of substrate proteins including transcription factors and other protein kinases
  • MEKs appear specific and sole activators of MAPKs and could act as a focal point for cross-cascade regulation.
  • MEK1 and MEK2 isoforms show unusual specificity and also contain a proline-rich insert between catalytic subdomains LX and X which is not present in any of the other known MEK family members.
  • 3-cyanoquinoline derivatives are useful in the treatment of cancer.
  • Certain of the compounds are stated to be inhibitors of EGF receptor tyrosine kinase, others are stated to be inhibitors of the mitogen-activated protein kinase (MAPK) pathway and others are stated to be inhibitors of growth factors such as vascular endothelial growth factor (VEGF).
  • MAPK mitogen-activated protein kinase
  • VEGF vascular endothelial growth factor
  • Z is an O, S, SO, SO 2 , N(R 2 ) or C(R 2 ) 2 group, wherein each R 2 group, which may be the same or different, is hydrogen or (l-6C)alkyl; m is O, 1, 2, 3 or 4; each R 1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsul ⁇ hinyl, (l-6C)alkylsul ⁇ honyl,
  • (l-6C)alkylamino di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl- (3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)
  • X is a direct bond or is selected from CO and N(R )CO, wherein R is hydrogen or (l-6C)alkyl, and Q 2 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (l-6C)al
  • any aryl, heteroaryl or heterocyclyl group within a substituent on R 1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)
  • X 4 is a direct bond or is selected from O and N(R 9 ), wherein R 9 is hydrogen or
  • R 8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino- (l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, or from a group of the formula : -X 5 -Q 4 wherein X 5 is a direct bond or is selected from O, N(R 10 ) and CO, wherein R 10 is hydrogen or (l-6C)alkyl, and Q 4 is aryl, aryl-(l-6C)alkyl, heteroaryl, hetero
  • X 6 is a direct bond or is selected from O and N(R 12 ), wherein R 12 is hydrogen or (l-6C)alkyl, and R 11 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl or di-[(l-6C)alkyl]amino-(l-6C)alkyl, or from a group of the formula :
  • X 7 is a direct bond or is selected from O, S, SO, SO 2 , N(R 13 ), CO, CH(OR 13 ), CON(R 13 ), N(R 13 )CO, SO 2 N(R 13 ), N(R 13 )SO 2 , C(R 13 ) 2 O, C(R 13 ) 2 S and N(R 13 )C(R 13 ) 2 , wherein R 13 is hydrogen or (l-6C)alkyl, and Q 5 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and any heterocyclyl group within
  • a method for producing an anti-proliferative effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a quinoline derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of MEK enzymes that are involved in the MAPK pathway.
  • Particular enzymes that the tumours may be sensitive to are MEK 1, MEK 2 and MEK 5.
  • a method for the prevention or treatment of those tumours which are sensitive to inhibition of MEK enzymes that are involved in the MAPK pathway which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically- acceptable salt thereof, as defined hereinbefore.
  • a quinoline derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a MEK enzyme inhibitory effect.
  • a method for providing a MEK enzyme inhibitory effect which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a novel quinoline derivative of Formula I as hereinbefore defined, where Z, m and R 1 are as hereinbefore defined, n is 1, 2 or 3 and at least one R 3 is formyl, or a pharmaceutically-acceptable salt.
  • alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-7C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • references to individual alkyl groups such as "propyl” are specific for the straight-chain version only
  • references to individual branched-chain alkyl groups such as "isopropyl” are specific for the branched-chain version only
  • references to individual cycloalkyl groups such as "cyclopentyl” are specific for that 5-membered ring only.
  • (l-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy
  • (l-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino
  • di-[(l-6Calkyl]amino includes dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl- N-ethylamino.
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • Suitable values for the generic radicals referred to above include those set out below.
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 5 ) when it is aryl or for the aryl group within a 'Q' group is, for example, phenyl or naphthyl, preferably phenyl.
  • a suitable value for any one of the 'Q' groups (Q or Q ) when it is (3-7C)cycloalkyl or for the (3-7C)cycloalkyl group within a 'Q' group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl and a suitable value for any one of the 'Q' groups (Q 1 or Q 3 ) when it is (3-7C)cycloalkenyl or for the (3-7C)cycloalkenyl group within a 'Q' group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 5 ) when it is heteroaryl or for the heteroaryl group within a 'Q' group is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, .
  • benzothienyl benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl.
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 5 ) when it is heterocyclyl or for the heterocyclyl group within a 'Q' group is, for example, a non-aromatic saturated or partially saturated 3 to 10 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro- 1,4-thiazinyl, l,l-dioxot
  • a suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
  • a suitable value for a 'Q' group when it is heteroaryl-(l-6C)alkyl is, for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl.
  • the invention comprises corresponding suitable values for 'Q' groups when, for example, rather than a heteroaryl-(l-6C)alkyl group, an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group is present.
  • Suitable values for any of the 'R' groups (R 1 to R 13 ) or for various groups within an R 1 or R 3 substituent include :- for halogeno fluoro, chloro, bromo and iodo; for (l-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (2-8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for (l-6C)alkylthio: methylthio
  • N-methylethanesulphonylamino 10 for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; for N-(l-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and N-methylcrotonamido; for (3-6C)alkynoylamino: propiolamido; for N-(l-6C)alkyl-(3-6C)alkynoylamino: N-methylpropiolamido; for amino-(l-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and
  • an R 1 group forms a group of the formula Q ⁇ X 1 - and, for example, X 1 is a OC(R 4 ) 2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R 4 ) 2 linking group which is attached to the quinoline ring and the oxygen atom is attached to the Q 1 group.
  • adjacent carbon atoms in any (2-6C)alkylene chain within a R 1 substituent may be optionally separated by the insertion into the chain of a group such as O, CON(R 5 ) or C ⁇ C.
  • a group such as O, CON(R 5 ) or C ⁇ C.
  • insertion of a C ⁇ C group into the ethylene chain within a 2-morpholinoethoxy group gives rise to a 4-morpholinobut-2-ynyloxy group and, for example, insertion of a CONH group into the ethylene chain within a 3-methoxypropoxy group gives rise to, for example, a 2-(2-methoxyacetamido)ethoxy group.
  • suitable R 1 substituents so formed include, for example, N-[heterocyclyl-
  • (l-6C)alkyl]carbamoylvinyl groups such as N-(2-pyrrolidin-l-ylethyl)carbamoylvinyl or N-[heterocyclyl-(l-6C)alkyl]carbamoylethynyl groups such as N-(2-pyrrolidin- 1 -ylethyl)carbamoylethynyl.
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more halogeno or (l-6C)alkyl substituents, there are suitably 1 or 2 halogeno or (l-6C)alkyl substituents present on each said CH 2 group and there are suitably 1, 2 or 3 such substituents present on each said CH 3 group.
  • R 1 substituents so formed include, for example, hydroxy-substituted heterocyclyl- (l-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy- 3-morpholinopropoxy, hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino- 2-hydroxypropoxy, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkoxy groups such as 2-hydroxy-3-methylaminopropoxy, hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkoxy groups such as 3-dimethylamino-2-hydroxypropoxy, hydroxy-substituted heterocyclyl- (l-6C)alkylamino groups such as 2-hydroxy-3-piperid
  • a suitable pharmaceutically-acceptable salt of a compound of the Formula I for use according to the invention is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an acid-addition salt of a compound of the Formula I for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid
  • Particular compounds of Formula I or pharmaceutically acceptable salts thereof for use according to the invention include, for example, quinoline derivatives of the Formula I wherein, unless otherwise stated, each of Z, m, R 1 , n and R 3 has any of the meanings defined hereinbefore or in paragraphs (a) to (q) hereinafter :-
  • each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoyla
  • X 1 is a direct bond or is selected from O, N(R 4 ), CON(R 4 ), N(R 4 )CO and OC(R 4 ) 2 wherein R 4 is hydrogen or (l-6C)alkyl
  • X is a direct bond or is CO or N(R )CO, wherein R is hydrogen or (l-6C)alkyl, and Q 2 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more halogeno groups or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyloxy, (2-6C)alkanoylamino and N-(l-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula : -X 3 -Q 3 wherein X 3 is a direct bond or is CO or N(
  • X 5 is a direct bond or is selected from O, N(R 10 ) and CO, wherein R 10 is hydrogen or (l-6C)alkyl, and Q 4 is heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo substituents;
  • each R 1 group which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, vinyl, allyl, but-3-enyl, pent-4-enyl, hex-5-enyl, ethynyl, 2-propynyl, but-3-ynyl, pent-4-ynyl, hex-5-ynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, allyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy, ethynyloxy, 2-propynyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, propyla
  • X 1 is a direct bond or is selected from O, NH, CONH, NHCO and OCH 2 and Q 1 is phenyl, benzyl, cyclopropylmethyl, 2-thienyl, 1-imidazolyl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, 2-, 3- or 4-pyridyl, 2-imidazol-l-ylethyl, 3-imidazol-l-ylpropyl,
  • Q 2 -X 2 - wherein X 2 is a direct bond or is CO, NHCO or N(Me)CO and Q 2 is pyridyl, pyridylmethyl, 2-pyridylethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, ⁇ yrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl,
  • 3-pyrrolidin-l-ylpropyl 4-pyrrolidin-l-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl,
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido or from a group of the formula
  • X 4 is a direct bond or is selected from O and NH and R 8 is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from a group of the formula :
  • X 5 is a direct bond or is selected from O, NH and CO and Q 4 is pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl,
  • m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and each R 1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and
  • R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, pyrrolidin-1-yl, piperidino, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, cyclopropyl
  • X 2 is a direct bond or is NHCO or N(Me)CO and Q 2 is imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidin
  • N-methylcarbamoyl, N,N-dimethylcarbamoyl and methoxy, and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R 1 substituent is optionally N-substituted with allyl, 2-propynyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl,
  • (g) m is 1 and the R 1 group is located at the 6- or 7-position and is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, benzyloxy, 2-imidazol-l-ylethoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, 2-pyrrolidin- 1 -ylethoxy , 3-pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy , pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-y
  • n is 1 or 2 and the R 3 groups, which may be the same or different, are located at the 3-, 5- and/or 6-positions of the benzofuran-4-yl group and are selected from halogeno, trifluoromethyl, cyano, hydroxy, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy;
  • n is 1 or 2 and the R 3 groups, which may be the same or different, are located at the 3-, 5- and/or 6-positions of the benzofuran-4-yl group and are selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, methoxy and ethoxy, (k) n is 1 and the R group is located at the
  • each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino and N-(l-6C)alkyl- (2-6C)alkanoylamino, or from a group of the formula :
  • X 1 is selected from O, N(R 4 ), CON(R 4 ), N(R 4 )CO and OC(R 4 ) 2 wherein R 4 is hydrogen or (l-6C)alkyl
  • Q 1 is aryl, aryl-(l-6C)alkyl, cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or X 1 is a direct bond and Q 1 is aryl-(l-6C)alkyl, cycloalkyl-(l-6C)alkyl, heteroaryl-(l-6C)alkyl or heterocyclyH 1 -6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R 1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R ), CON(R 5 )
  • X 3 is a direct bond or is selected from O, N(R 6 ), CON(R 7 ), N(R 7 )CO and C(R 7 ) 2 O, wherein R is hydrogen or (l-6C)alkyl, and Q is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R 1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsulphonyl, N-(l-6C)alkylcarbamoyl,
  • X 4 is a direct bond or is selected from O and N(R 9 ), wherein R 9 is hydrogen or (l-6C)alkyl, and R 8 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, and from a group of the formula :
  • X 5 is a direct bond or is selected from O, N(R 10 ) and CO, wherein R 10 is hydrogen or (l-6C)alkyl, and Q 4 is heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo substituents;
  • each R 1 group which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetamido, propiona ido, acrylamido and propiolamido, or from a group of the formula :
  • X 1 is selected from O, NH, CONH, NHCO and OCH 2 and Q 1 is phenyl, benzyl, cyclopropylmethyl, 2-thienyl, 1-imidazolyl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, 2-, 3- or 4-pyridyl, 2-imidazol-l-ylethyl, 3-imidazol-l-ylpropyl, 2-(l,2,3-triazolyl)ethyl,
  • X 3 is a direct bond or is selected from O, NH, CONH, NHCO and CH 2 O and Q 3 is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, pyrrolidin- 2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin- 3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperidin
  • X is a direct bond or is selected from O and NH and R is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl,
  • (n) m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and each R 1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and
  • R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol-l -ylethoxy, 3-imidazol-l -ylpropoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 3-(l,2,3-triazol-l-yl)propoxy, 2-(l,2,4-triazol-l-yl-yl
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido, and wherein any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, N
  • n is 1 or 2 and the R 3 groups, which may be the same or different, are located at the 3-, 5- 6-and/or 7-positions of the benzofuran-4-yl group and are selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl,
  • n 1 and the R 3 group is located at the 5- or 6-position of the benzofuran-4-yl group, especially the 5-position, and is selected from chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy.
  • novel compounds for use according to the invention include, for example, quinoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, R , n and R has any of the meanings defined hereinbefore provided that :- (A) R 1 substituents may only be located at the 5-, 6- and/or 7-positions on the quinoline ring i.e. the 2- and 8-positions remain unsubstituted; or
  • R 1 substituents may only be located at the 6- and/or 7-positions on the quinoline ring i.e. the 2-, 5- and 8-positions remain unsubstituted.
  • a further aspect of the invention is the use of a quinoline of Formula I wherein : Z is O or NH;
  • R 1 1 m is 1 and the R group is located at the 5-, 6- or 7-position or m is 2 and each R group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-l -ylethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin- 1 -ylethoxy, 3-pyrrolidin- 1 -y
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy; and wherein any heteroaryl or heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl and N,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperid
  • a particular aspect of the invention is the use of a quinoline derivative of the Formula I wherein : Z is O or NH; m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and each R 1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-l -ylethoxy, 2-( 1 ,2,4-triazol- 1 -yl)ethoxy, tetrahydrofuran-3-yloxy, tetrahydro
  • N,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R 1 substituent is optionally N-substituted with allyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-l-ylethyl or 3-
  • a further aspect of the invention is the use of a quinoline of Formula I wherein: Z is O or NH; m is 2 and the first R 1 group is located at the 6-position and is selected from hydroxy, methoxy, ethoxy and propoxy, and the second R 1 group is located at the 7-position and is selected from 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, 2-methoxyethoxy, 3-methoxypropoxy, 4-methoxybutoxy, 2-(2-hydroxyethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropy
  • a further aspect of the invention is the use of a quinoline of Formula I wherein
  • a further aspect of the invention is the use of a quinoline derivative of the Formula I wherein : Z is O or NH;
  • 1 1 m is 2 and the first R group is a 6-methoxy group and the second R group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy,
  • any CH 2 group within the second R 1 group that is attached to two carbon atoms optionally bears a hydroxy group on said CH 2 group
  • any heteroaryl group within the second R 1 group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl
  • any heterocyclyl group within the second R 1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo
  • n is 0 or n is 1 and the R group, if present, is located at the 6-position of the benzofuran-4-yl group and is selected from fluoro, chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
  • a further aspect of the invention is the use of a quinoline of Formula I wherein: Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy,
  • 3-piperidin-4-ylpropoxy 3-(N-methylpiperidin-4-yl)propoxy, 2-(l,2,3,6-tetrahydropyridin- l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-(l,2,3,6-tetrahydropyridin- l-yl)butoxy, 2-(4-hydroxypiperidin-l-yl)ethoxy, 3-(4-hydroxypiperidin-l-yl)propoxy, 4-(4-hydroxypiperidin-l-yl)butoxy, 2-piperazin-l -ylethoxy, 3-piperazin-l-ylpropoxy, 4-piperazin-l -ylbutoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 4-(4-methylpiperazin- 1 -yl)butoxy, 3-(4-allyl
  • a further aspect of the invention is the use of a quinoline derivative of the Formula I wherein :
  • Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-pipe
  • n 0 or n is 1 and the R 3 group, if present, is located at the 6-position of the benzofuranyl group and is selected from chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
  • a further aspect of the invention is the use of a quinoline of Formula I wherein Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3-(l , l-dioxotetrahydro-4H-l ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3 -y
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from methoxy, ethoxy, 2-pyrroridin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(l,2,3,6-tetrahydropyridin- l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-
  • Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from methoxy, 3-morpholinopropoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy, 3-(l,2,3,6-tetrahydropyridin- l-yl)propoxy, 4-(l,2,3,6-tetrahydropyridin-l-yl)butoxy, 3-(4-hydroxypiperidin- 1 -yl)propoxy, 3 -piperazin- 1 -ylpropoxy, 3-(4-methylpiperazin-l-yl)propoxy, 4-(4-methylpiperazin-l-yl)butoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 3-(4-acetylpiperazin-l-yl)propoxy,
  • n 0 or n is 1 and the R 3 group, if present, is located at the 5- or 6-position of the benzofuranyl group and is selected from fluoro, chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
  • a further aspect of the invention is the use of a quinoline derivative of the Formula I wherein :
  • Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylrnethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin
  • a further aspect of the invention is the use of a quinoline of Formula I wherein
  • Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(l , l-dioxotetrahydro-4H-l ,4-thiazin- 4-yl)ethoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3
  • n 0 or n is 1 and the R group, if present, is located at the 6-position of the benzofuran-4-yl group and is selected from chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
  • a further aspect of the invention is the use of a quinoline of Formula I wherein
  • Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 3-(4-methylpiperazin-l-yl)propoxy, n is 1 and the R 3 group is a chloro or bromo group located at the 6-position of the benzofuran-4-yl group, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
  • a further aspect of the invention is the use of a quinoline of Formula I selected from :• 4-(6-chlorobenzofuran-4-ylamino)-3-cyano-6-methoxy-7-[3-(4-methylpiperazin- l-yl)propoxy]quinoline and
  • a further aspect of the invention is the use of a quinoline dervative of Formula I wherein Z is O or NH; m is 1 and the R 1 group is located at the 5-position and is selected from tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3-yloxy,
  • a further aspect of the invention is the use of a quinoline derivative of Formula I wherein : m is 2 and the first R 1 group is located at the 5-position and is selected from tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3-yloxy, l,l-dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy, l,l-dioxotetrahydrothiopyran-4-yloxy, N-methylazetidin-3-yloxy, N-ethylazetidin-3-yloxy, N-isopropylazetidin-3-yloxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, N-methylpiperidin-3-yloxy, 4-
  • a further aspect of the invention is the use of a quinoline of Formula I wherein : m is 2 and the first R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, N-methylpyrrolidin-3-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second R 1 is located at the 7-position and is selected from methoxy, benzyloxy, 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-piperidinoethoxy,
  • n 0 or n is 1 and the R 3 group, if present, is located at the 6-position of the benzofuran-4-yl group and is selected from chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
  • a further aspect of the invention is the use of a quinoline of Formula I wherein : m is 2 and the first R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second R 1 is located at the 7-position and is selected from methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy,
  • n 0 or n is 1 and the R 3 group, if present, is located at the 6-position of the benzofuran-4-yl group and is selected from chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
  • a further aspect of the invention is the use of a quinoline of Formula I
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is NH; m is 1 and the R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, and the second R 1 group is located at the 7-position and is selected from methoxy, ethoxy, propoxy, 3-pyrrolidin- 1 -ylpropoxy, 3-piperidinopropoxy, 3-morpholinopropoxy, 3-piperazin-l-ylpropoxy and 3-(4-methylpiperazin-l-yl)propoxy; n is 0 or n is 1 and the R 3 group, if present, is a chloro group located at the 5-position of
  • a further aspect of the invention is the use of a quinoline of Formula I wherein :
  • Z is NH; m is 1 and the R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy and N-methylpiperidin-4-yloxy, and the second R 1 group is located at the 7-position and is selected from methoxy and 3-morpholinopropoxy; and n is O, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
  • a further aspect of the invention is the use of a quinoline of Formula I selected from:-
  • a further aspect of the invention is the use of a quinoline of Formula I selected from:- 4-(5-chlorobenzofuran-4-ylamino)-3-cyano-7-methoxy-5-(N-methylpiperidin-
  • 5-tetrahydropyran-4-yloxyquinoline or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
  • a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, for use according to the invention may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes are illustrated by the following representative process variants in which, unless otherwise stated, m, R 1 , Z, n and R 3 have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • L is a displaceable group and m and R 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the Formula HI
  • R and R have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
  • a suitable acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • a suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydr
  • the quinoline of the Formula II may be reacted with a compound of the Formula HI in the presence of an aprotic solvent such as N,N-dimethylformamide, conveniently in the presence of a base, for example potassium carbonate or sodium hexamethyldisilazane, and at a temperature in the range, for example, 0 to 150°C, preferably in the range, for example, 0 to 70°C.
  • an aprotic solvent such as N,N-dimethylformamide
  • a base for example potassium carbonate or sodium hexamethyldisilazane
  • the quinoline derivative of the Formula I may be obtained from this process in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of the formula H-L wherein L has the meaning defined hereinbefore.
  • the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • a suitable base for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diaza
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • a carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy- lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); tri(lower alkyl)silyl-(
  • hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
  • tri(lower alkyl)silyl for example trimethylsilyl and tert-butyldimethylsilyl
  • aryl-lower alkyl for example benzyl
  • amino protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example methylidene) and benzylidene and substituted benzylidene groups.
  • aryl-lower alkyl groups for example benzy
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as 2-nitrobenzyloxycarbonyl.
  • groups such as 2-nitrobenzyloxycarbonyl
  • hydrogenation for groups such as benzyl
  • photolytically for groups such as 2-nitrobenzyloxycarbonyl.
  • the reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents and to Protective Groups in Organic Synthesis, 2 nd Edition, by T. Green et al, also published by John Wiley & Son, for general guidance on protecting groups.
  • Quinoline starting materials of the Formula II may be obtained by conventional procedures such as those disclosed in International Patent Applications WO 98/43960 and WO 00/68201.
  • a l,4-dihydroquinolin-4-one of Formula IV wherein m and R 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary may be reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed by conventional means.
  • a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed by conventional means.
  • the 4-chloroquinoline so obtained may be converted, if required, into a 4-pentafluorophenoxyquinoline by reaction with pentafluorophenol in the presence of a suitable base such as potassium carbonate and in the presence of a suitable solvent such as N,N-dimethylformamide.
  • a suitable base such as potassium carbonate
  • a suitable solvent such as N,N-dimethylformamide.
  • 4-Aminobenzofuran starting materials (Formula HJ, for example when Z is NH) may be obtained by conventional procedures as illustrated in the Examples.
  • Corresponding 4-hydroxybenzofuran and 4-mercaptobenzofuran starting materials may be obtained by conventional procedures, (b) For the production of those compounds of the Formula I wherein at least one R 1 group is a group of the formula wherein Q 1 is an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl- (l-6C)alkyl, heteroaryl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group or an optionally substituted alkyl group and X 1 is an oxygen atom, the coupling, conveniently in the presence of a suitable dehydrating agent, of a quinoline of the Formula V
  • m, R 1 , Z, n and R 3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an appropriate alcohol wherein any functional group is protected if necessary whereafter any protecting group that is present is removed by conventional means.
  • a suitable dehydrating agent is, for example, a carbodiimide reagent such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of an azo compound such as diethyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
  • a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride
  • L is a displaceable group as defined hereinbefore and Z, n and R 3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an alcohol or amine as appropriate.
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 50°C.
  • a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 50°C.
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
  • the cleavage reaction may conveniently be carried out, for example, by treatment of the quinoline derivative with a boron or aluminium trihalide such as boron tribromide.
  • the cleavage reaction of a compound of the Formula I wherein R 1 is a arylmethoxy group may be carried out, for example, by hydrogenation of the quinoline derivative in the presence of a suitable metallic catalyst such as palladium or by reaction with an organic or inorganic acid, for example trifluoroacetic acid.
  • Such reactions are preferably carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
  • Suitable protecting groups for an amino group are, for example, any of the protecting groups disclosed hereinbefore for an amino group. Suitable methods for the cleavage of such amino protecting groups are also disclosed hereinbefore.
  • a suitable protecting group is a lower alkoxycarbonyl group such as a tert-butoxycarbonyl group which may be cleaved under conventional reaction conditions such as under acid-catalysed hydrolysis, for example in the presence of trifluoroacetic acid.
  • a suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy to alkoxy or substituted alkoxy, or for the alkylation of amino to alkylamino or substituted alkylamino, for example an alkyl or substituted alkyl halide, for example a (l-6C)alkyl chloride, bromide or iodide or a substituted (l-6C)alkyl chloride, bromide or iodide, conveniently in the presence of a suitable base as defined hereinbefore, in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 140°C, conveniently at or near ambient temperature.
  • an alkyl or substituted alkyl halide for example a (l-6C)alkyl chloride, bromide or iodide or a substituted (l-6C)alkyl chloride, bromide or iodide, conveniently in the presence
  • a suitable reducing agent is, for example, a hydride reducing agent, for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride.
  • a hydride reducing agent for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride.
  • the reaction is conveniently performed in a suitable inert solvent or diluent, for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
  • a suitable inert solvent or diluent for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
  • reaction is performed at a temperature in the range, for example, 10 to 80°C, conveniently at or near ambient temperature, (h)
  • R 1 is an amino-hydroxy-disubstituted (l-6C)alkoxy group (such as 2-hydroxy-3-pyrrolidin- 1-ylpropoxy or 3-[N-allyl-N-methylamino]-2-hydroxypropoxy)
  • the reaction of a compound of the Formula I wherein the R 1 group contains an epoxy-substituted (l-6C)alkoxy group with a heterocyclyl compound or an appropriate amine is an amino-hydroxy-disubstituted (l-6C)alkoxy group.
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
  • Suitable protecting groups for a hydroxy group are, for example, any of the protecting groups disclosed hereinbefore. Suitable methods for the cleavage of such hydroxy protecting groups are also disclosed hereinbefore.
  • a suitable protecting group is a lower alkanoyl group such as an acetyl group which may be cleaved under conventional reaction conditions such as under base-catalysed conditions, for example in the presence of ammonia, (j) For the production of those compounds of the Formula I wherein Z is a SO or SO 2 group, the oxidation of a compound of Formula I wherein Z is a S group.
  • a compound of the Formula I wherein an R 1 or R 3 substituent is a halogeno group may be reacted with a metal cyanide to form a compound of the Formula I wherein an R 1 or R 3 substituent is a cyano group.
  • the reaction may be carried out in the presence of a suitable catalyst.
  • a suitable metal cyanide is, for example, a heavy metal cyanide such as zinc cyanide.
  • a suitable catalyst is, for example, an organometallic reagent, for example an organoiron compound such as diphenylphosphinoferrocene.
  • the conversion reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 100°C.
  • a compound of the Formula I wherein an R 1 or R 3 substituent is a halogeno group may be reacted with a (2-6C)alkyne to form a compound of the Formula I wherein an R 1 or R 3 substituent is a (2-6C)alkynyl group such as an ethynyl group.
  • the reaction may conveniently be carried out in the presence of a suitable base as defined hereinbefore and in the presence of a suitable catalyst.
  • a suitable catalyst is, for example, an organometallic reagent, for example an organopalladium compound such as tetrakis(triphenylphosphine)palladium(0).
  • the conversion reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 60°C.
  • a compound of the Formula I wherein an R 1 or R 3 substituent is a halogeno group may be reacted with an arylboron reagent to form a compound of the
  • R or R substituent is an aryl group such as a phenyl group.
  • a suitable arylboron reagent is, for example, an arylboronic acid.
  • the reaction may conveniently be carried out in the presence of a suitable catalyst, for example, an organopalladium compound such as tetrakis(triphenylphosphine)palladium(0).
  • the conversion reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 80°C.
  • a pharmaceutically-acceptable salt of a quinoline derivative of the Formula I for use according to the invention it may be obtained by, for example, reaction of said quinoline derivative with a suitable acid using a conventional procedure.
  • the following assays can be used to measure the effects of the compounds as inhibitors of the MAPK pathway.
  • Assay to detect MEK inhibition can be used to measure the effects of the compounds as inhibitors of the MAPK pathway.
  • a coupled assay was carried out which measures phosphorylation of serine/threonine residues present in the substrate in the presence or absence of inhibitor.
  • Recombinant glutathione S-transferase fusion protein containing human p45MEKl (GST-MEK) was activated by c-raf (Sf9 insect cell lysate from triple baculoviral infection with c-raf/ras/lck) and used for the assay.
  • Active GST-MEK was first used to activate a recombinant glutathione S-transferase fusion protein containing p44MAP kinase (GST-MAPK) in the presence of ATP and Mg 2+ for 60min at room temperature in the presence or absence of potential inhibitors.
  • GST-MAPK was then incubated with myelin basic protein (MBP) as substrate for lOmin at room temperature in the presence of ATP, Mg 2+ and 33 P-ATP.
  • MBP myelin basic protein
  • the reaction was stopped by addition of 20% v/v phosphoric acid.
  • Incorporation of 33 P into the myelin basic protein was determined by capture of the substrate on a filter mat, washing and counting using scintillation methods. The extent of inhibition was determined by comparison with untreated controls.
  • the final assay solution contained lOmM Tris, pH 7.5, 0.05mM EGTA, 8.33 ⁇ M
  • GST-MAPK was activated by a constitutively active GST-MEK fusion protein containing two point mutations (S217E, S221E) and used for the assay in the presence and absence of potential inhibitors.
  • the activated GST-MAPK was incubated with substrate (MBP) for 60min at room temperature in the presence of ATP, Mg 2+ and 33 P-ATP. The reaction was stopped by addition of 20% v/v phosphoric acid. Incorporation of 33 P into the myelin basic protein was determined by capture of the substrate on a filter mat, washing and counting using scintillation methods.
  • the final assay solution contained 12mM Tris, pH 7.5, 0.06mM EGTA, 30 ⁇ M [ ⁇ 33 P]ATP, lOmM Mg(OAc) 2 , 0.6mM sodium orthovanadate, 0.06%w/v BSA, 28ng GST-MAPK and 16.5 ⁇ g MBP in a reaction volume of 60 ⁇ l.
  • Compounds of Formula I showed activity in this screen.
  • Cell proliferation assays Cells were seeded into multi-well plates at 20000 - 40 000 cells/ml in growth medium containing 5% FCS and incubated overnight at 37°C. The compounds were prepared in fresh medium at an appropriate concentration and added to the wells containing the cells. These were then incubated for a further 72 hours. Cells were then either removed from the wells by incubating with trypsin/EDTA and counted using a Coulter counter, or treated with XTT PMS in PBS A and optical densities read at 450nm. Compounds of Formula I had IC 50 results typically less than 30/xM.
  • a pharmaceutical composition for the use of compounds of Formula I according to the invention comprises a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
  • a pharmaceutical compositon which comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier for use as an anti- proliferative agent in the containment and/or treatment of solid tumour disease.
  • compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration is however preferred, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • anti-proliferative treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumour agents :-
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol
  • Agents which inhibit cancer cell invasion for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
  • inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [HerceptinTM] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethyny
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy
  • immunotherapy approaches including for example ex- vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of the Formula I within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • a pharmaceutical product comprising a quinoline derivative of the Formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the use in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
  • the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of MEK enzyme. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the Formula I were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture;
  • Example 1 The compound in the Example below was found to be active in the assays described above.
  • Example 1 The compound in the Example below was found to be active in the assays described above.
  • the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent.
  • the material so obtained was dissolved in diethyl ether and a solution of hydrogen chloride in diethyl ether (1M, 2 ml) was added.
  • the resultant solid was washed with diethyl ether and dried.
  • the methyl 3-allyloxybenzoate so obtained was heated to 200°C for 0.7 hours and then to 230°C for 1 hour.
  • the reaction product comprising a mixture of methyl 2-allyl- 3-hydroxybenzoate and methyl 4-allyl-3-hydroxybenzoate, was cooled to ambient temperature and partitioned between diethyl ether and IN aqueous potassium hydroxide solution.
  • the aqueous phase was allowed to stand for 30 minutes whereupon the methyl 4-allyl- 3-hydroxybenzoate was hydrolysed to 4-allyl-3-hydroxybenzoic acid.
  • the aqueous phase was then acidified to pHl by the addition of 6N aqueous hydrochloric acid and extracted with diethyl ether.
  • the organic extract was washed with 10% aqueous potassium carbonate solution, dried over magnesium sulphate and evaporated. There was thus obtained methyl 2-allyl-3-hydroxybenzoate (10.7 g) as an oil; Mass Spectrum: M+H 192.
  • Trifluoroacetic acid (2.5 ml) was added to a solution of tert-butyl benzofuran- 4-carbamate (0.65 g) and methylene chloride (20 ml) which had been cooled to 0°C and the mixture was stirred for lhour. The mixture was allowed to warm to ambient temperature and stirring was continued for 1.5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulphate and evaporated. The resultant oil was purified by column chromatography using a 4: 1 mixture of methylene chloride and petroleum ether (b.p. 60-80°C) as eluent.
  • Diethyl azodicarboxylate (0.25 g) was added dropwise to a suspension of 4-chloro- 3-cyano-7-hydroxy-6-methoxyquinoline (0.2 g; , prepared as described in International Patent Application WO 00/68201, disclosed as compound (7) within Preparation 1 therein), l-(3-hydroxypropyl)-4-methylpiperazine (0.202 g), triphenyl phosphine (0.447 g) and methylene chloride (5 ml) and the mixture was stirred at ambient temperature for 2 hours.
  • the resultant mixture was evaporated and the residue was purified by column chromatography on silica using initially increasingly polar mixtures of methylene chloride and ethyl acetate followed by increasingly polar mixtures of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent.
  • the material so obtained was triturated under diethyl ether.
  • Compound X a representative pharmaceutical dosage form of the invention as defined herein (the active ingredient being termed "Compound X”), for therapeutic or prophylactic use in humans:
  • Maize starch paste (5% w/v paste) 2.25
  • the above formulation may be obtained by conventional procedures well known in the pharmaceutical art.
  • the tablet may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

Abstract

The invention concerns the use of a quinoline derivative of the Formula I, wherein each of Z, m, R1, n and R3 have any of the meanings defined hereinbefore in the description, in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING BENZOFURANYL SUBSTITUTED -CYANOQUINOLINE DERIVATIVES AND THEIR USE FOR THE TREATMENT OF SOLID TUMOURS
The invention concerns a new use of novel quinoline derivatives, or pharmaceutically-acceptable salts thereof, which have been found to possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body. Cancer is a disease in which cells grow and divide in an uncontrolled fashion. This uncontrolled growth arises from abnormalities in signal transduction pathways that are used by normal cells to regulate cell growth and division in response to various signalling molecules. Normal cells do not proliferate unless stimulated to do so by specific signal molecules located outside the cell derived from nearby cells or tissues. Growth factors bind to the cell membrane via specific receptors which have intrinsic enzyme activity. These receptors relay the growth signal to the cell nucleus via a series of signalling proteins, hi cancer, a number of defects in signal pathways are apparent. For example, cancer cells may produce their own growth factors which bind to their cognate receptors, resulting in an autocrine loop, or receptors may be mutated or overexpressed leading to an increased, continuous signal to proliferate. In addition, negative regulators of cell growth may be lost. Oncogenes are cancer related genes which often encode abnormal versions of signal pathway components, such as receptor tyrosine kinases, serine-threonine kinases, or downstream signaling molecules such as the ras genes, which code for closely related small guanine nucleotide binding proteins which hydrolyse bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Ras proteins are active in promoting cell growth and transformation when they are bound to GTP and inactive when they are bound to GDP. Transforming mutants of p2 Iras are defective in their GTPase activity and hence remain in the active GTP bound state. The ras oncogene is known to play an integral role in certain cancers, and has been found to contribute to the formation of over 20% of all cases of human cancer. When activated by ligand, cell surface receptors which are coupled to the mitogenic response, such as growth factor receptors, initiate a chain of reactions which leads to the activation of guanine nucleotide exchange activity on ras. When in its active GTP-bound state, a number of proteins interact directly with ras at the plasma membrane resulting in signal transmission through several distinct pathways. The best characterised effector protein is the product of the raf proto-oncogene. The interaction of raf and ras is a key regulatory step in the control of cell proliferation. Ras-mediated activation of the raf serine-threonine kinase in turn activates the dual-specificity MEK (MEK1 and MEK2), which is the immediate upstream activator of mitogen activated protein kinase (MAPKs known as extracellular signal regulated protein kinases or ERK1 and ERK2). To date, no substrates of MEK other than MAPK have been identified, though recent reports indicate that MEK may also be activated by other upstream signal proteins such as MEKKl and Cot/Tpl-2. Activated MAPK translocates and accumulates in the nucleus, where it can phosphorylate and activate transcription factors such as Elk-1 and Sapla, leading to the enhanced expression of genes such as that for c-fos.
The ras-dependent raf-MEK-MAPK cascade is one of the key signalling pathways responsible for transmitting and amplifying mitogenic signals from cell surface to the nucleus resulting in changes in gene expression and cell fate. This ubiquitous pathway appears essential for normal cell proliferation and constitutive activation of this pathway is sufficient to induce cellular transformation. Transforming mutants of p21ras are constitutively active, resulting in raf, MEK and MAPK activity and cell transformation. Inhibition of MEK activity using either antisense raf, a dominant negative MEK mutant or the selective inhibitor PD098059 have been shown to block the growth and morphological transformation of ras-transformed fibroblasts.
The mechanism of activation of raf, MEK and MAPK is through phosphorylation on specific serine, threonine or tyrosine residues. Activated raf and other kinases phosphorylate MEK1 on S218 and S222 and MEK2 on S222 and S226. This results in MEK activation and subsequent phosphorylation and activation of ERK1 on T190 and Y192 and ERK2 on T183 and Yl 85 by the dual specificity MEKs. Whilst MEK can be activated by a number of protein kinases, and active MAPKs phosphorylate and activate a number of substrate proteins including transcription factors and other protein kinases, MEKs appear specific and sole activators of MAPKs and could act as a focal point for cross-cascade regulation. MEK1 and MEK2 isoforms show unusual specificity and also contain a proline-rich insert between catalytic subdomains LX and X which is not present in any of the other known MEK family members. These differences between MEK and other protein kinases, together with the known role of MEK (MEK 1, MEK 2) and, more recently, MEK 5 in proliferative signalling suggest that it may be possible to discover and employ selective MEK inhibitors as therapeutic agents for use in proliferative disease. It is stated in International Patent Application WO 98/43960 that a range of
3-cyanoquinoline derivatives are useful in the treatment of cancer. Certain of the compounds are stated to be inhibitors of EGF receptor tyrosine kinase, others are stated to be inhibitors of the mitogen-activated protein kinase (MAPK) pathway and others are stated to be inhibitors of growth factors such as vascular endothelial growth factor (VEGF). There is no disclosure therein of any 4-benzofuranylamino-3-cyanoquinoline derivatives.
It is stated in International Patent Application WO 00/68201 that a range of 3-cyanoquinoline derivatives are also useful in the treatment of cancer. Certain of the compounds are stated to be inhibitors of MEK, a MAPK kinase. There is no disclosure therein of any 4-benzofuranylamino-3-cyanoquinoline derivatives.
It is also stated in WO 00/18761 that a range of 3-cyanoquinoline derivatives are also useful in the treatment of cancer. Certain of the compounds are stated to be inhibitors of MEK, a MAPK kinase. There is no disclosure therein of any 4-benzofuranylamino-3- cyanoquinoline derivatives.
According to one aspect of the invention there is provided the use of a quinoline derivative of the Formula I
Figure imgf000004_0001
wherein Z is an O, S, SO, SO2, N(R2) or C(R2)2 group, wherein each R2 group, which may be the same or different, is hydrogen or (l-6C)alkyl; m is O, 1, 2, 3 or 4; each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulρhinyl, (l-6C)alkylsulρhonyl,
(l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl- (3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulρhonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula : Q^X1 - wherein X1 is a direct bond or is selected from O, S, SO, SO2, N(R4), CO, CH(OR4), CON(R4), N(R4)CO, SO2N(R4), N(R4)SO2, OC(R4)2, SC(R4)2 and N(R4)C(R4)2, wherein R4 is hydrogen or (l-6C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or (R^m is (l-3C)alkylenedioxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)CO, SO2N(R5), N(R5)SO2, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyl]amino-(l-6C)alkyl or from a group of the formula :
Q2-X2- wherein X is a direct bond or is selected from CO and N(R )CO, wherein R is hydrogen or (l-6C)alkyl, and Q2 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl- (2-6C)alkanoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulρhonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula : -X3-Q3 wherein X3 is a direct bond or is selected from O, S, SO, SO2, N(R7), CO, CH(OR7), CON(R7), N(R7)CO, SO2N(R7), N(R7)SO2, C(R7)2O, C(R7)2S and N(R7)C(R7)2, wherein R7 is hydrogen or (l-6C)alkyl, and Q3 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-
(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, N-(l-6C)alkylsulρhamoyl, N,N-di-[(l-6C)alkyl]sulρhamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl- (l-6C)alkanesulphonylamino, or from a group of the formula :
-X4-R8 wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or
(l-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino- (l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, or from a group of the formula : -X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents; n is O, 1, 2 or 3; and R is halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, carboxy, carbamoyl,
(l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl- (3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
-X6-Rπ wherein X6 is a direct bond or is selected from O and N(R12), wherein R12 is hydrogen or (l-6C)alkyl, and R11 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl or di-[(l-6C)alkyl]amino-(l-6C)alkyl, or from a group of the formula :
-X7-Q5 wherein X7 is a direct bond or is selected from O, S, SO, SO2, N(R13), CO, CH(OR13), CON(R13), N(R13)CO, SO2N(R13), N(R13)SO2, C(R13)2O, C(R13)2S and N(R13)C(R13)2, wherein R13 is hydrogen or (l-6C)alkyl, and Q5 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and any heterocyclyl group within Q5 optionally bears 1 or 2 oxo or thioxo substituents, or a pharmaceutically-acceptable salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
According to a further feature of the invention there is provided a method for producing an anti-proliferative effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
According to a further aspect of the invention there is provided the use of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of MEK enzymes that are involved in the MAPK pathway. Particular enzymes that the tumours may be sensitive to are MEK 1, MEK 2 and MEK 5. According to a further feature of this aspect of the invention there is provided a method for the prevention or treatment of those tumours which are sensitive to inhibition of MEK enzymes that are involved in the MAPK pathway which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically- acceptable salt thereof, as defined hereinbefore.
According to a further aspect of the invention there is provided the use of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a MEK enzyme inhibitory effect. According to a further feature of this aspect of the invention there is provided a method for providing a MEK enzyme inhibitory effect which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
According to a further aspect of the invention there is provided a novel quinoline derivative of Formula I, as hereinbefore defined, where Z, m and R1 are as hereinbefore defined, n is 1, 2 or 3 and at least one R3 is formyl, or a pharmaceutically-acceptable salt.
In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-7C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only, references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only and references to individual cycloalkyl groups such as "cyclopentyl" are specific for that 5-membered ring only. An analogous convention applies to other generic terms, for example (l-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy, (l-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino, and di-[(l-6Calkyl]amino includes dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl- N-ethylamino.
It is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
Suitable values for the generic radicals referred to above include those set out below. A suitable value for any one of the 'Q' groups (Q1 to Q5) when it is aryl or for the aryl group within a 'Q' group is, for example, phenyl or naphthyl, preferably phenyl.
A suitable value for any one of the 'Q' groups (Q or Q ) when it is (3-7C)cycloalkyl or for the (3-7C)cycloalkyl group within a 'Q' group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl and a suitable value for any one of the 'Q' groups (Q1 or Q3) when it is (3-7C)cycloalkenyl or for the (3-7C)cycloalkenyl group within a 'Q' group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
A suitable value for any one of the 'Q' groups (Q1 to Q5) when it is heteroaryl or for the heteroaryl group within a 'Q' group is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, . benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl.
A suitable value for any one of the 'Q' groups (Q1 to Q5) when it is heterocyclyl or for the heterocyclyl group within a 'Q' group is, for example, a non-aromatic saturated or partially saturated 3 to 10 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro- 1,4-thiazinyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl, preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, l,l-dioxotetrahydro-4H- 1,4-thiazinyl, piperidinyl or piperazinyl. A suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. A suitable value for a 'Q' group when it is heteroaryl-(l-6C)alkyl is, for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl. The invention comprises corresponding suitable values for 'Q' groups when, for example, rather than a heteroaryl-(l-6C)alkyl group, an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group is present.
In structural Formula I there is a hydrogen atom at the 2-position on the quinoline ring. It is to be understood thereby that the R1 substituents may only be located at the 5-, 6-, 7- or 8-positions on the quinoline ring i.e. that the 2-position remains unsubstituted. It is further to be understood that the R3 group that may be present on the benzofuranyl group within structural Formula I may be located on either the 5- or 6-membered ring portions thereof, for example at the 2-, 3-, 4-, 5- or 6-positions of the benzofuran-4-yl group.
Suitable values for any of the 'R' groups (R1 to R13) or for various groups within an R1 or R3 substituent include :- for halogeno fluoro, chloro, bromo and iodo; for (l-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (2-8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for (l-6C)alkylthio: methylthio, ethylthio and propylthio; for (l-6C)alkylsulphinyl: methylsulphinyl and ethylsulphinyl; for (l-6C)alkylsulphonyl: methylsulphonyl and ethylsulphonyl; for (l-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-[(l-6C)alkyl]amino: dimethylamino, diethylamino, N-ethyl- N-methylamino and diisopropylamino; for (l-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for N-(l-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl ; for N,N-di-[(l-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl, N-ethyl- N-methylcarbamoyl and N,N-diethylcarbamoyl; for (2-6C)alkanoyl: acetyl and propionyl; for (2-6C)alkanoyloxy: acetoxy and propionyloxy; for (2-6C)alkanoylamino: aceta ido and propionamido; for N-(l-6C)alkyl-(2-6C)alkanoylamino: N-methylacetamido and N-methylpropionamido; 5 for N-(l-6C)alkylsulphamoyl: N-methylsulphamoyl and N-ethylsulphamoyl; for N,N-di-[(l-6C)alkyljsulphamoyl: N,N-dimethylsulphamoyl; for (l-6C)alkanesulphonylamino: methanesulphonylamino and ethanesulphonylamino; for N-(l-6C)alkyl-(l-6C)alkanesulphonylamino: N-methylmethanesulphonylamino and
N-methylethanesulphonylamino ; 10 for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; for N-(l-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and N-methylcrotonamido; for (3-6C)alkynoylamino: propiolamido; for N-(l-6C)alkyl-(3-6C)alkynoylamino: N-methylpropiolamido; for amino-(l-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and
15 3-aminopropyl; for (l-6C)alkylamino-(l-6C)alkyl: methylaminomethyl, ethylaminomethyl,
1-methylaminoethyl, 2-methylaminoethyl,
2-ethylaminoethyl and 3-methylaminopropyl; for di-[(l-6C)alkyl]amino-(l-6C)alkyl: dimethylaminomethyl, diethylaminomethyl,
20 1-dimethylaminoethyl, 2-dimethylaminoethyl and
3-dimethylaminopropyl; for halogeno-(l-6C)alkyl: chloromethyl, 2-chloroethyl, 1-chloroethyl and
3-chloropropyl; for hydroxy-(l-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and
25 3-hydroxypropyl; for (l-6C)alkoxy-(l-6C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl,
2-methoxyethyl, 2-ethoxyethyl and
3-methoxypropyl; for cyano-(l-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and
30 3-cyanopropyl; for (2-6C)alkanoylamino-(l-6C)alkyl: acetamidomethyl, propionamidoniethyl and
2-acetamidoethyl; and for (l-6C)alkoxycarbonylamino-(l-6C)alkyl: methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and 2-methoxycarbonylaminoethyl. A suitable value for (R^m when it is a (l-3C)alkylenedioxy group is, for example, methylenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.
When, as defined hereinbefore, an R1 group forms a group of the formula Q^X1- and, for example, X1 is a OC(R4)2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R4)2 linking group which is attached to the quinoline ring and the oxygen atom is attached to the Q1 group. Similarly, when, for example a CH3 group within a R1 substituent bears a group of the formula -X3-Q3 and, for example, X3 is a C(R7)2O linking group, it is the carbon atom, not the oxygen atom, of the C(R7)2O linking group which is attached to the CH3 group and the oxygen atom is linked to the Q3 group. A similar convention applies to the attachment of the groups of the formulae Q2-X2- and -X7-Q5.
As defined hereinbefore, adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent may be optionally separated by the insertion into the chain of a group such as O, CON(R5) or C≡C. For example, insertion of a C≡C group into the ethylene chain within a 2-morpholinoethoxy group gives rise to a 4-morpholinobut-2-ynyloxy group and, for example, insertion of a CONH group into the ethylene chain within a 3-methoxypropoxy group gives rise to, for example, a 2-(2-methoxyacetamido)ethoxy group.
When, as defined hereinbefore, any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent such as a group of the formula Q2~X2- wherein X2 is, for example, NHCO and Q2 is a heterocyclyl-(l-6C)alkyl group, suitable R1 substituents so formed include, for example, N-[heterocyclyl-
(l-6C)alkyl]carbamoylvinyl groups such as N-(2-pyrrolidin-l-ylethyl)carbamoylvinyl or N-[heterocyclyl-(l-6C)alkyl]carbamoylethynyl groups such as N-(2-pyrrolidin- 1 -ylethyl)carbamoylethynyl.
When, as defined hereinbefore, any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents, there are suitably 1 or 2 halogeno or (l-6C)alkyl substituents present on each said CH2 group and there are suitably 1, 2 or 3 such substituents present on each said CH3 group. When, as defined hereinbefore, any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group a substituent as defined hereinbefore, suitable R1 substituents so formed include, for example, hydroxy-substituted heterocyclyl- (l-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy- 3-morpholinopropoxy, hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino- 2-hydroxypropoxy, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkoxy groups such as 2-hydroxy-3-methylaminopropoxy, hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkoxy groups such as 3-dimethylamino-2-hydroxypropoxy, hydroxy-substituted heterocyclyl- (l-6C)alkylamino groups such as 2-hydroxy-3-piperidinopropylamino and 2-hydroxy- 3-morpholinopropylamino, hydroxy-substituted amino-(2-6C)alkylamino groups such as 3 -amino-2-hydroxypropylamino, hydroxy-substituted ( 1 -6C)alkylamino-(2-6C)alkylamino groups such as 2-hydroxy-3-methylaminopropylamino, hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkylamino groups such as 3-dimethylamino- 2-hydroxypropylamino, hydroxy-substituted (l-6C)alkoxy groups such as 2-hydroxyethoxy, (l-6C)alkoxy-substituted (l-6C)alkoxy groups such as 2-methoxyethoxy and 3-ethoxypropoxy, (l-6C)alkylsulphonyl-substituted (l-6C)alkoxy groups such as 2-methylsulphonylethoxy and heterocyclyl-substituted (l-6C)alkylamino-(l-6C)alkyl groups such as 2-morpholinoethylaminomethyl, 2-piperazin-l-ylethylaminomethyl and 3-morpholinopropylaminomethyl. A suitable pharmaceutically-acceptable salt of a compound of the Formula I for use according to the invention is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
Particular compounds of Formula I or pharmaceutically acceptable salts thereof for use according to the invention include, for example, quinoline derivatives of the Formula I wherein, unless otherwise stated, each of Z, m, R1, n and R3 has any of the meanings defined hereinbefore or in paragraphs (a) to (q) hereinafter :-
(a) Z is O, S, SO, SO2, CH2 or NH;
(b) Z is O; (c) Z is NH;
(d) m is 1 or 2, and each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino and N-(l-6C)alkyl- (3-6C)alkynoylamino, or from a group of the formula :
O^-X1 - wherein X1 is a direct bond or is selected from O, N(R4), CON(R4), N(R4)CO and OC(R4)2 wherein R4 is hydrogen or (l-6C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, cycloalkyl- (l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R5), CON(R5), N(R5)CO, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl, or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from carbamoyl, N-( 1 -6C)alkylcarbamoyl, N,N-di- [( 1 -6C)alkyl]carbamoyl, amino-( 1 -6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl and di-[(l-6G)alkyl]amino-(l-6C)alkyl or from a group of the formula :
Q2-X2- wherein X is a direct bond or is CO or N(R )CO, wherein R is hydrogen or (l-6C)alkyl, and Q2 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno groups or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyloxy, (2-6C)alkanoylamino and N-(l-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula : -X3-Q3 wherein X3 is a direct bond or is selected from O, N(R6), CON(R7), N(R7)CO and C(R7)2O, wherein R7 is hydrogen or (l-6C)alkyl, and Q3 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsulρhonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoyl, or optionally bears 1 substituent selected from a group of the formula : -X4-R8 wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (l-6C)alkyli and R8 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, and from a group of the formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(e) m is 1 or 2, and each R1 group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, vinyl, allyl, but-3-enyl, pent-4-enyl, hex-5-enyl, ethynyl, 2-propynyl, but-3-ynyl, pent-4-ynyl, hex-5-ynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, allyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy, ethynyloxy, 2-propynyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetamido, propionamido, acrylamido and propiolamido, or from a group of the formula :
Q^X1 - wherein X1 is a direct bond or is selected from O, NH, CONH, NHCO and OCH2 and Q1 is phenyl, benzyl, cyclopropylmethyl, 2-thienyl, 1-imidazolyl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, 2-, 3- or 4-pyridyl, 2-imidazol-l-ylethyl, 3-imidazol-l-ylpropyl,
2-(l ,2,3-triazolyl)ethyl, 3-(l ,2,3-triazolyl)propyl, 2-(l ,2,4-triazolyl)ethyl, 3-(l,2,4-triazolyl)propyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or 4-pyridyl)propyl, tetrahydrofuran-3-yl, 3- or 4-tetrahydropyranyl, 1-, 2- or 3-pyrrolidinyl, morpholino, l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl, piperidino, piperidin-3-yl, piperidin-4-yl, 1-, 3- or 4-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or 4-homopiperidinylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethyl, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin- 4-yl)propyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, 2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl, 2-homopiperidin-l-ylethyl, 3-homopiperidin-l-ylpropyl, 2-piperazin-l-ylethyl, 3-piperazin-l-ylpropyl, 4-piperazin-l-ylbutyl, 2-homopiperazin-l-ylethyl or 3 -homopiperazin- 1 -ylpropyl , and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(Me), CONH, NHCO, CH=CH and C≡C, and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl or 4-dimethylaminobutyl, or from a group of the formula :
Q2-X2- wherein X2 is a direct bond or is CO, NHCO or N(Me)CO and Q2 is pyridyl, pyridylmethyl, 2-pyridylethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, ρyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl,
3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl,
4-piperidinobutyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-l-ylethyl, 3-piperazin-l-ylpropyl or 4-piperazin- 1 -ylbutyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido or from a group of the formula : -X3-Q3 wherein X3 is a direct bond or is selected from O, NH, CONH, NHCO and CH2O and Q3 is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, pyrrolidin- 2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin- 3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-l-ylethyl or 3-piperazin- l-ylpropyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl, methoxy, methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl, or optionally bears 1 substituent selected from a group of the formula :
-X4-R8 wherein X4 is a direct bond or is selected from O and NH and R8 is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from a group of the formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, NH and CO and Q4 is pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl,
3-piperidinopropyl, piperazin-1-ylmethyl, 2-piperazin-l-ylethyl or 3-piperazin-l-ylpropyl, each of which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; and
(f) m is 1 and the R1 group is located at the 5-, 6- or 7-position or m is 2 and each R1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and
7-positions and R1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, pyrrolidin-1-yl, piperidino, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol-l-ylethoxy, 3-imidazol-l-ylpropoxy, 2-(l,2,3-triazol-l-yl)ethoxy,
3-(l ,2,3-triazol- 1 -yl)propoxy, 2-( 1 ,2,4-triazol- 1 -yl)ethoxy, 3-( 1 ,2,4-triazol- l-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin-l-ylpropoxy, 4-pyrrolidin-l-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3-( 1 , 1 -dioxotetrahydro- 4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin-l-ylethoxy, 3-homopiperidin-l-ylpropoxy, 2-piperazin- 1 -ylethoxy , 3-piperazin- 1 -ylpropoxy , 4-piperazin- 1 -ylbutoxy , 2-homopiperazin-l-ylethoxy, 3-homopiperazin-l-ylpropoxy, 2-pyrrolidin-l-ylethylamino, 3-pyrrolidin-l-ylpropylamino, 4-pyrrolidin-l-ylbutylamino, pyrrolidin-3-ylamino, pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino, 3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 4-morpholinobutylamino, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethylamino, 3-(l,l-dioxotetrahydro- 4H- 1 ,4-thiazin-4-yl)propylamino, 2-piperidinoethylamino, 3-piperidinopropylamino,
4-piperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperidin-3-ylmethylamino, 2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino, 2-piperidin-4-ylethylamino, 2-homopiperidin-l-ylethylamino, 3-homopiperidin-l-ylpropylamino, 2-piperazin-l-ylethylamino, 3-piperazin-l-ylpropylamino, 4-piperazin-l-ylbutylamino, 2-homopiperazin-l-ylethylamino or 3 -homopiperazin- 1 -ylpropyl amino , and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(Me), CH=CH and C≡C, and when R1 is a vinyl or ethynyl group, the R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from N-(2-dimethylaminoethyl)carbarnoyl, N-(3-dimethylaminopropyl)carbamoyl, methylaminornethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl and 4-dimethylaminobutyl, or from a group of the formula :
Q2-X2- wherein X2 is a direct bond or is NHCO or N(Me)CO and Q2 is imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-l-ylethyl, 3-piperazin-l-ylpropyl or 4-piperazin-l-ylbutyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido, and wherein any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl,
N-methylcarbamoyl, N,N-dimethylcarbamoyl and methoxy, and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R1 substituent is optionally N-substituted with allyl, 2-propynyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl,
2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-l-ylethyl or 3-piperazin-l-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents.
(g) m is 1 and the R1 group is located at the 6- or 7-position and is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, benzyloxy, 2-imidazol-l-ylethoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, 2-pyrrolidin- 1 -ylethoxy , 3-pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy , pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy , 3-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, 2-piperidin-3 -ylethoxy, piperidin-4-ylmethoxy , 2-piperidin-4-ylethoxy, 2-homopiperidin- 1 -ylethoxy, 3-homopiperidin-l-ylpropoxy, 2-piperazin-l -ylethoxy, 3-piperazin-l-ylpropoxy, 2-homopiperazin-l -ylethoxy or 3-homopiperazin-l -ylpropoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, CH=CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino and acetoxy, and wherein any phenyl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl and methoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; (h) n is O;
(i) n is 1 or 2 and the R3 groups, which may be the same or different, are located at the 3-, 5- and/or 6-positions of the benzofuran-4-yl group and are selected from halogeno, trifluoromethyl, cyano, hydroxy, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy; (j) n is 1 or 2 and the R3 groups, which may be the same or different, are located at the 3-, 5- and/or 6-positions of the benzofuran-4-yl group and are selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, methoxy and ethoxy, (k) n is 1 and the R group is located at the 5- or 6-position of the benzofuran-4-yl group, especially the 6-position, and is selected from chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy,
(1) m is 1 or 2, and each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino and N-(l-6C)alkyl- (2-6C)alkanoylamino, or from a group of the formula :
Q^X1 - wherein X1 is selected from O, N(R4), CON(R4), N(R4)CO and OC(R4)2 wherein R4 is hydrogen or (l-6C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or X1 is a direct bond and Q1 is aryl-(l-6C)alkyl, cycloalkyl-(l-6C)alkyl, heteroaryl-(l-6C)alkyl or heterocyclyH 1 -6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R ), CON(R5), N(R5)CO, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl, or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno groups or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (2-6C)alkanoyloxy, (2-6C)alkanoylamino andN-(l-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula :
-X3-Q3 wherein X3 is a direct bond or is selected from O, N(R6), CON(R7), N(R7)CO and C(R7)2O, wherein R is hydrogen or (l-6C)alkyl, and Q is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsulphonyl, N-(l-6C)alkylcarbamoyl,
N,N-di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoyl, or optionally bears 1 substituent selected from a group of the formula :
-X4-R8 wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, and from a group of the formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(m) m is 1 or 2, and each R1 group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetamido, propiona ido, acrylamido and propiolamido, or from a group of the formula :
Q^-X1 - wherein X1 is selected from O, NH, CONH, NHCO and OCH2 and Q1 is phenyl, benzyl, cyclopropylmethyl, 2-thienyl, 1-imidazolyl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, 2-, 3- or 4-pyridyl, 2-imidazol-l-ylethyl, 3-imidazol-l-ylpropyl, 2-(l,2,3-triazolyl)ethyl,
3-(l,2,3-triazolyl)propyl, 2-(l,2,4-triazolyl)ethyl, 3-(l,2,4-triazolyl)propyl, 2-, 3- or
4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or 4-pyridyl)propyl, tetrahydrofuran-3-yl, 3- or 4-tetrahydropyranyl, 1-, 2- or 3-pyrrolidinyl, morpholino, l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl, piperidino, piperidin-3-yl, piperidin-4-yl, 1-, 3- or
4-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or
4-homopiperidinylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl,
2-(l , l-dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethyl, 3-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, 2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl, 2-homopiperidin-l-ylethyl, 3-homopiperidin-l-ylpropyl, 2-(l,2,3,6-tetrahydropyridin-l- yl)ethyl, 3-(l,2,3,6-tetrahydropyridin-l-yl)propyl, 4-(l,2,3,6-tetrahydropyridin-l-yl)butyl, 2-piperazin-l-ylethyl, 3-piperazin-l-ylpropyl, 4-ρiperazin-l-ylbutyl, 2-homopiperazin-l-ylethyl or 3-homopiperazin-l-ylpropyl, or wherein X1 is a direct bond and Q1 is benzyl, cyclopropylmethyl, 2-imidazol-l-ylethyl, 3-imidazol-l-ylpropyl, 2-(l,2,3-triazolyl)ethyl, 3-(l,2,3-triazolyl)propyl, 2-(l,2,4-triazolyl)ethyl, 3-(l,2,4-triazolyl)propyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or 4-pyridyl)propyl, 1-, 2- or 3-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or 4-homopiperidinylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl,
2-(l , l-dioxotetrahydro-4H-l ,4-thiazin-4-yl)ethyl, 3-(l , l-dioxotetrahydro-4H-l ,4-thiazin- 4-yl)propyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, 2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl, 3-piperidin-4-ylproρyl, 2-homopiperidin-l-ylethyl, 3-homopiperidin-l-ylpropyl, 2-piperazin-l-ylethyl, 3-piperazin-l-ylpropyl, 4-piperazin-l-ylbutyl, 2-homopiperazin-l-ylethyl or 3 -homopiperazin- 1 -ylpropyl , and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(Me), CONH, NHCO, CH=CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido or from a group of the formula :
-X3-Q3 wherein X3 is a direct bond or is selected from O, NH, CONH, NHCO and CH2O and Q3 is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, pyrrolidin- 2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin- 3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-l-ylethyl or 3-piperazin- l-ylpropyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl, methoxy, methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl, or optionally bears 1 substituent selected from a group of the formula :
-X4-R8 wherein X is a direct bond or is selected from O and NH and R is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl,
3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from a group of the formula : -X5-Q4 wherein X5 is a direct bond or is selected from O, NH and CO and Q4 is pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, piperazin-1-ylmethyl, 2-piperazin-l-ylethyl or 3-piperazin-l-ylpropyl, each of which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(n) m is 1 and the R1 group is located at the 5-, 6- or 7-position or m is 2 and each R1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and
7-positions and R1 is selected from hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol-l -ylethoxy, 3-imidazol-l -ylpropoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 3-(l,2,3-triazol-l-yl)propoxy, 2-(l,2,4-triazol-l-yl)ethoxy, 3-(l,2,4-triazol-l-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3 -ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy,
3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 4-pyrrolidin-l-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethoxy, 3-(l,l-dioxotetrahydro- 4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3 -ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin- 1 -ylethoxy, 3-homopiperidin- 1 -ylpropoxy, 2-(l,2,3,6-tetrahydropyridin-l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-(l,2,3,6-tetrahydropyridin-l-yl)butoxy, 2-piperazin-l -ylethoxy, 3-piperazin-l-ylpropoxy, 4-piperazin- 1 -ylbutoxy , 2-homopiperazin- 1 -ylethoxy, 3 -homopiperazin- 1 -ylpropoxy, 2-pyrrolidin- 1 -ylethylamino, 3 -pyrrolidin- 1 -ylpropylamino, 4-pyrrolidin- 1 -ylbutylamino, pyrrolidin-3-ylamino, pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino, 3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 4-morpholinobutylamino, 2-(l , l-dioxotetrahydro-4H-l ,4-thiazin-4-yl)ethylamino, 3 -( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 4-piperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperidin-3-ylmethylamino, 2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino, 2-piperidin-4-ylethylamino, 2-homopiperidin-l-ylethylamino,
3-homopiperidin-l-ylpropylamino, 2-(l,2,3,6-tetrahydropyridin-l-yl)ethylamino,
3 -( 1 ,2,3 ,6-tetrahydropyridin- 1 -yl)propylamino, 4-( 1 ,2,3 ,6-tetrahydropyridin- 1 -yl)butylamino,
2-piperazin-l-ylethylamino, 3-piperazin-l-ylpropylamino, 4-piperazin-l-ylbutylamino, 2-homopiperazin-l-ylethylamino or 3-homopiperazin-l-ylpropylamino, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH,
N(Me), CH=CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido, and wherein any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl and methoxy, and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R1 substituent is optionally N-substituted with methyl, ethyl, propyl, allyl, 2-propynyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-fluoroethyl, 3-fluoropropyl, 2-chloroethyl, 3-chloropropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-l-ylethyl or 3-piperazin-l-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; (o) n is 1 or 2 and the R3 groups, which may be the same or different, are selected from halogeno, trifluoromethyl, cyano, hydroxy, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy;
(p) n is 1 or 2 and the R3 groups, which may be the same or different, are located at the 3-, 5- 6-and/or 7-positions of the benzofuran-4-yl group and are selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl,
1-propynyl, 2-propynyl, methoxy and ethoxy; and
(q) n is 1 and the R3 group is located at the 5- or 6-position of the benzofuran-4-yl group, especially the 5-position, and is selected from chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy.
Further particular novel compounds for use according to the invention include, for example, quinoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, R , n and R has any of the meanings defined hereinbefore provided that :- (A) R1 substituents may only be located at the 5-, 6- and/or 7-positions on the quinoline ring i.e. the 2- and 8-positions remain unsubstituted; or
(B) R1 substituents may only be located at the 6- and/or 7-positions on the quinoline ring i.e. the 2-, 5- and 8-positions remain unsubstituted.
A further aspect of the invention is the use of a quinoline of Formula I wherein : Z is O or NH;
1 1 m is 1 and the R group is located at the 5-, 6- or 7-position or m is 2 and each R group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-l -ylethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin- 1 -ylethoxy, 3-pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l , l-dioxotetrahydro-4H-l ,4-thiazin-4-yl)ethoxy, 3-(l , 1-dioxotetrahydro-
4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3 -ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin-l -ylethoxy, 3-homopiperidin-l -ylpropoxy, 2-piperazin-l -ylethoxy, 3-piperazin-l-ylpropoxy, 4-piperazin-l -ylbutoxy, 2-homopiperazin-l -ylethoxy and 3-homopiperazin-l-ylpropoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH,
N(Me), CH=CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy; and wherein any heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl and N,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R1 substituent is optionally N-substituted with allyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-l-ylethyl or 3-piperazin-l-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; and n is 0 or 1 and the R3 group, if present, is located at the 3-, 5- or 6-position of the benzofuran-4-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy and ethoxy, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A particular aspect of the invention is the use of a quinoline derivative of the Formula I wherein : Z is O or NH; m is 1 and the R1 group is located at the 5-, 6- or 7-position or m is 2 and each R1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-l -ylethoxy, 2-( 1 ,2,4-triazol- 1 -yl)ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin- 1 -ylethoxy, 3-pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,
3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy , 3-( 1 , 1 -dioxotetrahydro- 4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy,
3-piperidin-4-ylpropoxy , 2-homopiperidin- 1 -ylethoxy, 3 -homopiperidin- 1 -ylpropoxy, 2-piperazin- 1 -ylethoxy, 3-piperazin- 1 -ylpropoxy, 4-piperazin- 1 -ylbutoxy, 2-homopiperazin-l -ylethoxy and 3-homopiperazin-l-ylpropoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(Me), CH=CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy; and wherein any heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl and
N,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R1 substituent is optionally N-substituted with allyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-l-ylethyl or 3-piperazin-l-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; and n is 0 or 1 and the R3 group, if present, is located at the 3-, 5- or 6-position of the benzofuran-4-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy and ethoxy, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline of Formula I wherein: Z is O or NH; m is 2 and the first R1 group is located at the 6-position and is selected from hydroxy, methoxy, ethoxy and propoxy, and the second R1 group is located at the 7-position and is selected from 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, 2-methoxyethoxy, 3-methoxypropoxy, 4-methoxybutoxy, 2-(2-hydroxyethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy, 3-(N-isopropyl-N-methylamino)propoxy, 4-(N-isopropyl-N-methylamino)butoxy, 2-(N-allylamino)ethoxy, 3-(N-allylamino)propoxy, 2-(N-allyl-N-methylamino)ethoxy, 3-(N-allyl-N-methylamino)propoxy, 2-(N-prop-2-ynylamino)ethoxy, 3-(N-prop-2~ynylamino)propoxy, 2-(N-methyl-N-prop-2-ynylamino)ethoxy, 3-(N-methyl-N-prop-2-ynylamino)propoxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,
3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,
N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy, 2-(4-methylpiperazin-l-yl)ethoxy,
3-(4-methylpiperazin-l-yl)propoxy, 4-(4-methylpiperazin-l-yl)butoxy, 2-(4-allylpiperazin- l-yl)ethoxy, 3-(4-allylpiperazin- 1 -yl)propoxy, 4-(4-allylpiperazin-l-yl)butoxy, 2-(4-methylsulphonylpiperazin-l-yl)ethoxy, 3-(4-methylsulphonylpiperazin-l-yl)propoxy, 4-(4-methylsulphonylpiperazin-l-yl)butoxy, 2-(4-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 4-(4-acetylpiperazin-l-yl)butoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3 -(4-cyanomethylpiperazin- 1 -yl)propoxy , 4-(4-cyanomethylpiperazin- 1 -yl)butoxy, 2- [2-(4-methylpiperazin-l-yl)ethoxy] ethoxy, 2-chloroethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy and 3-methylsulphonylpropoxy, and wherein any CH2 group within the second R1 group that is attached to two carbon atoms optionally bears a hydroxy group or acetoxy group on said CH_ group, and wherein any heterocyclyl group within the second R1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R3 group, if present, is located at the 5- or 6-position of the benzofuran-4-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline of Formula I wherein
Z is O or NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy,
4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy, 3-(N-isopropyl-N-methylamino)propoxy, 4-(N-isopropyl-N-methylamino)butoxy, 2-(N-isobutyl-N-methylamino)ethoxy, 3-(N-isobutyl-N-methylamino)propoxy, 4-(N-isobutyl-N-methylamino)butoxy, 2-(N-allyl-N-methylamino)ethoxy, 3-(N-allyl-N-methylamino)propoxy, 2-(N-prop-2-ynylamino)ethoxy, 3-(N-prop-2-ynylamino)propoxy, 2-(N-methyl-N-prop-2-ynylamino)ethoxy, 3-(N-methyl-N-prop-2-ynylamino)propoxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 4-pyrrolidin-l -ylbutoxy, pyrrolidin-3-yloxy,
N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l , l-dioxotetrahydro-4H-l ,4-thiazin-4-yl)ethoxy, 3-(l , 1-dioxotetrahydro- 4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, N-cyanomethylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, N-cyanomethylpiperidin-4-ylmethoxy, 2-piperidin-3 -ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy, 2-homopiperidin-l -ylethoxy, 3 -homopiperidin- 1 -ylpropoxy, 4-homopiperidin- 1 -ylbutoxy, 2-piperazin- 1 -ylethoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-piperazin-l-ylpropoxy, 3 -(4-methylpiperazin- 1 -yl)propoxy, 4-piperazin- 1 -ylbutoxy, 4-(4-methylpiperazin-l-yl)butoxy, 2-(4-allylpiperazin-l-yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 4-(4-allylpiperazin-l-yl)butoxy, 2-(4-methylsulphonylpiperazin-l-yl)ethoxy, 3-(4-methylsulphonylpiperazin-l-yl)propoxy, 4-(4-methylsulphonylpiperazin-l-yl)butoxy, 2-(4-acetylpiperazin-l-yl)ethoxy, 3 -(4-acetylpiperazin- 1 -yl)propoxy, 4-(4-acetylpiperazin- 1 -yl)butoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 4-(4-cyanomethylpiperazin-l-yl)butoxy, 2-(2-piperazin-l-ylethoxy)ethoxy, 2- [2-(4-methylpiperazin-l-yl)ethoxy] ethoxy, 2-chloroethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-tetrahydropyran-4-ylethoxy, 3-tetrahydropyran-4-ylpropoxy, 2-pyrrol-l -ylethoxy, 3-pyrrol-l-ylpropoxy, 2-(2-pyridyloxy)ethoxy, 3-(2-pyridyloxy)propoxy, 2-(3-pyridyloxy)ethoxy, 3-(3-pyridyloxy)propoxy, 2-(4-pyridyloxy)ethoxy, 3-(4-pyridyloxy)propoxy, 2-pyridylmethoxy, 3-pyridylmethoxy and 4-pyridylmethoxy, and wherein any CH2 group within the second R1 group that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heteroaryl group within the second R1 group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl, and any heterocyclyl group within the second R1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuran-4-yl group and is selected from fluoro, chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline derivative of the Formula I wherein : Z is O or NH;
1 1 m is 2 and the first R group is a 6-methoxy group and the second R group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy,
3-(N-isopropyl-N-methylamino)propoxy, 4-(N-isopropyl-N-methylamino)butoxy, 2-(N-isobutyl-N-methylamino)ethoxy, 3-(N-isobutyl-N-methylamino)propoxy, 4-(N-isobutyl-N-methylamino)butoxy, 2-(N-allyl-N-methylamino)ethoxy, 3-(N-allyl-N-methylamino)propoxy, 2-(N-prop-2-ynylamino)ethoxy, 3-(N-prop-2-ynylamino)propoxy, 2-(N-methyl-N-prop-2-ynylamino)ethoxy, 3 -(N-methyl-N-prop-2-ynylamino)propoxy, 2-pyrrolidin- 1 -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 4-pyrrolidin-l -ylbutoxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy , 3-( 1 , 1 -dioxotetrahydro-
4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, N-cyanomethylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, N-cyanomethylpiperidin-4-ylmethoxy,
2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yι)propoxy, 2-homopiperidin-l -ylethoxy,
3-homopiperidin- 1 -ylpropoxy, 4-homopiperidin- 1 -ylbutoxy, 2-piperazin- 1 -ylethoxy,
2-(4-methylpiperazin-l-yl)ethoxy, 3-piperazin-l-ylpropoxy,
3-(4-methylpiperazin- 1 -yl)propoxy, 4-piperazin- 1 -ylbutoxy, 4-(4-methylpiperazin- 1 -yl)butoxy, 2-(4-allylpiperazin- 1 -yl)ethoxy,
3-(4-allylpiperazin-l-yl)propoxy, 4-(4-allylpiperazin-l-yl)butoxy,
2-(4-methylsulphonylpiperazin-l-yl)ethoxy, 3-(4-methylsulphonylpiperazin-l-yl)propoxy,
4-(4-methylsulphonylpiperazin- 1 -yl)butoxy, 2-(4-acetylpiperazin- 1 -yl)ethoxy,
3-(4-acetylpiperazin-l-yl)propoxy, 4-(4-acetylpiperazin-l-yl)butoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy,
4-(4-cyanomethylpiperazin- 1 -yl)butoxy , 2-(2-piperazin- 1 -ylethoxy)ethoxy,
2-[2-(4-methylpiperazin-l-yl)ethoxy]ethoxy, 2-chloroethoxy, 3-chloropropoxy,
2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-tetrahydropyran-4-ylethoxy,
3 -tetrahydropyran-4-ylpropoxy, 2-pyrrol- 1 -ylethoxy, 3-pyrrol- 1 -ylpropoxy, 2-(2-pyridyloxy)ethoxy, 3-(2-pyridyloxy)propoxy, 2-(3-pyridyloxy)ethoxy,
3-(3-pyridyloxy)propoxy, 2-(4-pyridyloxy)ethoxy, 3-(4-pyridyloxy)propoxy,
2-pyridylmethoxy, 3-pyridylmethoxy and 4-pyridylmethoxy, and wherein any CH2 group within the second R1 group that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heteroaryl group within the second R1 group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl, and any heterocyclyl group within the second R1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R group, if present, is located at the 6-position of the benzofuran-4-yl group and is selected from fluoro, chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline of Formula I wherein: Z is NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy,
2-morpholinoethoxy, 3-morpholinopropoxy, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin- 4-yl)ethoxy, 3-( 1 , l-dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,
3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin- 3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy,
3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy, 2-(l,2,3,6-tetrahydropyridin- l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-(l,2,3,6-tetrahydropyridin- l-yl)butoxy, 2-(4-hydroxypiperidin-l-yl)ethoxy, 3-(4-hydroxypiperidin-l-yl)propoxy, 4-(4-hydroxypiperidin-l-yl)butoxy, 2-piperazin-l -ylethoxy, 3-piperazin-l-ylpropoxy, 4-piperazin-l -ylbutoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 4-(4-methylpiperazin- 1 -yl)butoxy, 3-(4-allylpiperazin- 1 -yl)propoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 3-(4-methylsulphonylpiperazin-l-yl)propoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 4-(4-acetylpiperazin-l-yl)butoxy, 3-[4-(2-fluoroethyl)piperazin-l-yl]propoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin- 1 -yl)propoxy, 2-[2-(4-methylpiperazin- 1 -yl)ethoxy]ethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; and n is 0 or n is 1 and the R group, if present, is located at the 5-, 6- or 7-position of the benzofuranyl group and is selected from fluoro, chloro, bromo and iodo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline derivative of the Formula I wherein :
Z is NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin- 3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy,
3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy,
2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy,
3-(4-allylpiperazin-l-yl)propoxy, 3-(4-methylsulphonylpiperazin-l-yl)propoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy,
3-(4-cyanomethylpiperazin-l-yl)propoxy, 2-[2-(4-methylpiperazin-l-yl)ethoxy]ethoxy,
3 -chloropropoxy, 2-methylsulphonylethoxy , 3-methylsulphonylpropoxy,
2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; and n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuranyl group and is selected from chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline of Formula I wherein Z is NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3-(l , l-dioxotetrahydro-4H-l ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3 -ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin- 3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiρeridin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy,
3-(4-allylpiperazin- 1 -yl)propoxy, 3-(4-methylsulphonylpiperazin- 1 -yl)propoxy, 3-(4-acetylpiρerazin-l-yl)propoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)ρropoxy, 2-[2-(4-methylpiperazin-l-yl)ethoxy]ethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; and n is 0 or n is 1 and the R group, if present, is located at the 6-position of the benzofuranyl group and is selected from chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from methoxy, ethoxy, 2-pyrroridin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(l,2,3,6-tetrahydropyridin- l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-(l,2,3,6-tetrahydropyridin- l-yl)butoxy, 2-(4-hydroxypiperidin-l-yl)ethoxy, 3-(4-hydroxypiperidin-l-yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 4-(4-methylpiperazin-l-yl)butoxy, 3 -(4-allylpiperazin- 1 -yl)propoxy, 3-(4-prop-2-ynylpiperazin- 1 -yl)propoxy, 3 -(4-acetylpiperazin- 1 -yl)propoxy , 4-(4-acetylpiperazin- 1 -yl)butoxy, 3-[4-(2-fluoroethyl)piperazin-l-yl]propoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy and 2-(2-methoxyethoxy)ethoxy; and n is 0 or n is 1 and the R3 group, if present, is located at the 5- or 6-position of the benzofuranyl group and is selected from fluoro, chloro, bromo and iodo; or a pharmaceutically-acceptable acid-addition salt thereof, in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease. A further aspect of the invention is the use of a quinoline derivative of the Formula I wherein :
Z is NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from methoxy, 3-morpholinopropoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy, 3-(l,2,3,6-tetrahydropyridin- l-yl)propoxy, 4-(l,2,3,6-tetrahydropyridin-l-yl)butoxy, 3-(4-hydroxypiperidin- 1 -yl)propoxy, 3 -piperazin- 1 -ylpropoxy, 3-(4-methylpiperazin-l-yl)propoxy, 4-(4-methylpiperazin-l-yl)butoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 3-(4-acetylpiperazin-l-yl)propoxy,
4-(4-acetylpiperazin-l-yl)butoxy, 3-[4-(2-fluoroethyl)piperazin-l-yl]propoxy,
3-chloropropoxy, 4-chlorobutoxy and 2-(2-methoxyethoxy)ethoxy; and n is 0 or n is 1 and the R3 group, if present, is located at the 5- or 6-position of the benzofuranyl group and is selected from fluoro, chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline derivative of the Formula I wherein :
Z is NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylrnethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin- 3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy,
2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 2-(4-cyanomethylpiperazin- 1 -yl)ethoxy, 3-(4-cyanomethylpiperazin- 1 -yl)propoxy, 2- [2-(4-methylpiperazin- 1 -yl)ethoxy] ethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; and n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuran-4-yl group and is selected from chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline of Formula I wherein
Z is NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(l , l-dioxotetrahydro-4H-l ,4-thiazin- 4-yl)ethoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin- 3 -yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy , 3 -(4-methylpiperazin- 1 -yl)propoxy,
2-(4-cyanomethylpiperazin- 1 -yl)ethoxy, 3 -(4-cyanomethylpiperazin- 1 -yl)propoxy, 2-[2-(4-methylpiperazin-l-yl)ethoxy]ethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; and n is 0 or n is 1 and the R group, if present, is located at the 6-position of the benzofuran-4-yl group and is selected from chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease. A further aspect of the invention is the use of a quinoline of Formula I wherein
Z is NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 3-(4-methylpiperazin-l-yl)propoxy, n is 1 and the R3 group is a chloro or bromo group located at the 6-position of the benzofuran-4-yl group, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline of Formula I selected from :• 4-(6-chlorobenzofuran-4-ylamino)-3-cyano-6-methoxy-7-[3-(4-methylpiperazin- l-yl)propoxy]quinoline and
4-benzofuran-7-ylamino-3-cyano-6-methoxy-7- [3 -(4-methylpiperazin- 1 -yl)proρoxy] quinoline, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline dervative of Formula I wherein Z is O or NH; m is 1 and the R1 group is located at the 5-position and is selected from tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3-yloxy,
1 , l-dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy,
1 , 1 -dioxotetrahydrothiopyran-4-yloxy, N-methylazetidin-3-yloxy, N-ethylazetidin-3-yloxy, N-isoproρylazetidin-3-yloxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, N-methylpiperidin-3-yloxy, 4-piperidinyloxy,
N-methylpiperidin-4-yloxy, N-allylpiperidin-4-yloxy, N-prop-2-ynylpiperidin-4-yloxy,
N-acetylpiperidin-4-yloxy, N-methylsulphonylpiperidin-4-yloxy,
N-(2-methoxyethyl)piperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, or m is 2 and the first R1 group is located at the 5-position and is selected from the group of substituents listed immediately above and the second R1 group is located at the
7-position and is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy, 2-pyrrolidin-l-ylethoxy,
3-pyrrolidin-l-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,
2-(l , l-dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-
4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-piperidin-4-ylethoxy,
2-(N-methylpiρeridin-4-yl)ethoxy, 2-homopiperidin- 1 -ylethoxy, 3-homopiperidin-l-ylpropoxy, 2-piperazin-l -ylethoxy, 3-piperazin-l-ylpropoxy,
2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy,
3-(4-cyanomethylpiperazin-l-yl)propoxy, 2-[(2S)-2-carbamoylpyrrolidin-l-yl]ethoxy,
2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-l-yl]ethoxy,
2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-l-yl]ethoxy, 2-tetrahydropyran-4-ylethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy,
2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-(4-pyridyloxy)ethoxy,
2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy and 3-cyanopyrid-4-ylmethoxy; and wherein any CH2 group within a R1 substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents, and wherein any CH2 group within a R1 substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH group; n is 0 or n is 1 and the R3 group, if present is located at the 3-, 5-, 6- or 7-position of the benzofuran-4-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline derivative of Formula I wherein : m is 2 and the first R1 group is located at the 5-position and is selected from tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3-yloxy, l,l-dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy, l,l-dioxotetrahydrothiopyran-4-yloxy, N-methylazetidin-3-yloxy, N-ethylazetidin-3-yloxy, N-isopropylazetidin-3-yloxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, N-methylpiperidin-3-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, N-allylpiperidin-4-yloxy, N-prop-2-ynylpiperidin-4-yloxy, N-acetylpiperidin-4-yloxy, N-methylsulphonylpiperidin-4-yloxy, N-(2-methoxyethyl)piperidin-4-yloxy, piperidin-3-ylmethoxy,
N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and the second R1 is located at the 7-position and is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy, 2-pyrrolidin- 1 -ylethoxy, 3-pyrrolidin- 1 -ylpropoxy, 2-morpholinoethoxy, 3 -morpholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy , 3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 2-homopiperidin- 1 -ylethoxy, 3-homopiperidin- 1 -ylpropoxy, 2-piperazin- 1 -ylethoxy, 3-piperazin- 1 -ylpropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiρerazin- 1 -yl)propoxy, 3-(4-cyanomethylpiperazin- 1 -yl)propoxy, 2-[(2S)-2-carbamoylpyrrolidin-l-yl]ethoxy, 2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-l- yl]ethoxy, 2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-l-yl]ethoxy, 2-tetrahydropyran-4-ylethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy and 3-cyanopyrid-4-ylmethoxy; and wherein any CH2 group within a R1 substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents, and wherein any CH2 group within a R1 substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group; n is 0 or n is 1 and the R3 group, if present is located at the 3-, 5- or 6-position of the benzofuran-4-yl group and is selected from fluoro, chloro, bromo; trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline of Formula I wherein : m is 2 and the first R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, N-methylpyrrolidin-3-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second R1 is located at the 7-position and is selected from methoxy, benzyloxy, 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-piperidinoethoxy,
3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(4-methylpiperazin- l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy and 3-methylsulphonylpropoxy; n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuran-4-yl group and is selected from chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline of Formula I wherein : m is 2 and the first R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second R1 is located at the 7-position and is selected from methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy,
2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 3-(4-hydroxypiperidin-l-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N4nethylpiperidin-4-yl)ethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-l-ylethoxy, 3-piperazin-l-ylpropoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy,
3-methylsulphonylpropoxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy; n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuran-4-yl group and is selected from chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline of Formula I
A further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is NH; m is 1 and the R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, and the second R1 group is located at the 7-position and is selected from methoxy, ethoxy, propoxy, 3-pyrrolidin- 1 -ylpropoxy, 3-piperidinopropoxy, 3-morpholinopropoxy, 3-piperazin-l-ylpropoxy and 3-(4-methylpiperazin-l-yl)propoxy; n is 0 or n is 1 and the R3 group, if present, is a chloro group located at the 5-position of the benzofuran-4-yl group, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline of Formula I wherein :
Z is NH; m is 1 and the R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy and N-methylpiperidin-4-yloxy, and the second R1 group is located at the 7-position and is selected from methoxy and 3-morpholinopropoxy; and n is O, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A further aspect of the invention is the use of a quinoline of Formula I selected from:-
4-(6-chlorobenzofuran-4-ylamino)-3-cyano-7-methoxy-5-(N-methylpiperidin- 4-yloxy)quinoline,
4-(6-chlorobenzofuran-4-ylamino)-3-cyano-7-(2-pyrrolidin-l-ylethoxy)- 5-tetrahydropyran-4-yloxyquinoline,
4-(6-chlorobenzofuran-4-ylamino)-3-cyano-7-(3-pyrrolidin-l-ylpropoxy)- 5-tetrahydropyran-4-yloxyquinoline, 4-(6-chlorobenzofuran-4-ylamino)-3-cyano-7-[3-(4-methylpiperazin-l-yl)propoxy]- 5-tetrahydropyran-4-yloxyquinoline,
4-(6-chlorobenzofuran-4-ylamino)-3-cyano-7-[2-(4-methylpiperazin-l-yl)ethoxy]- 5-tetrahydropyran-4-yloxyquinoline,
4-(6-chlorobenzofuran-4-ylamino)-3-cyano-7-(2-piperidinoethoxy)-5-tetrahydropyran- 4-yloxyquinoline and
4-(6-chlorobenzofuran-4-ylamino)-3-cyano-7-(N-methylpiperidin-4-ylmethoxy)- 5-tetrahydropyran-4-yloxyquinoline; or a pharmaceutically-acceptable acid-addition salt thereof, in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease
A further aspect of the invention is the use of a quinoline of Formula I selected from:- 4-(5-chlorobenzofuran-4-ylamino)-3-cyano-7-methoxy-5-(N-methylpiperidin-
4-yloxy)quinoline,
4-(5-chlorobenzofuran-4-ylamino)-3-cyano-7-(2-pyrrolidin-l-ylethoxy)-
5-tetrahydropyran-4-yloxyquinoline, 4-(5-chlorobenzofuran-4-ylamino)-3-cyano-7-(3-pyrrolidin-l-ylpropoxy)-
5-tetrahydropyran-4-yloxyquinoline,
4-(5-chlorobenzofuran-4-ylamino)-3-cyano-7-[3-(4-methylpiperazin-l-yl)propoxy]-
5-tetrahydropyran-4-yloxyquinoline,
4-(5-chlorobenzofuran-4-ylamino)-3-cyano-7-[2-(4-methylpiperazin-l-yl)ethoxy]- 5-tetrahydropyran-4-yloxyquinoline,
4-(5-chlorobenzofuran-4-ylamino)-3-cyano-7-(2-piperidinoethoxy)-5-tetrahydropyran-
4-yloxyquinoline and
4-(5-chlorobenzofuran-4-ylamino)-3-cyano-7-(N-nιethylpiperidin-4-ylmethoxy)-
5-tetrahydropyran-4-yloxyquinoline, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
A quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, for use according to the invention may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes are illustrated by the following representative process variants in which, unless otherwise stated, m, R1, Z, n and R3 have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
(a) For the production of those compounds of the Formula I wherein Z is an O, S or _.
N(R ), the reaction of a quinoline of the Formula II
Figure imgf000045_0001
wherein L is a displaceable group and m and R1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the Formula HI
Figure imgf000046_0001
" 9 wherein Z is O, S, or N(R ) and n, R and R have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
The reaction may conveniently be carried out in the presence of a suitable acid or in the presence of a suitable base. A suitable acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
A suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide. The reaction is conveniently carried out at a temperature in the range, for example, 0 to 250°C, preferably in the range 0 to 120°C.
Typically, the quinoline of the Formula II may be reacted with a compound of the Formula HI in the presence of an aprotic solvent such as N,N-dimethylformamide, conveniently in the presence of a base, for example potassium carbonate or sodium hexamethyldisilazane, and at a temperature in the range, for example, 0 to 150°C, preferably in the range, for example, 0 to 70°C.
The quinoline derivative of the Formula I may be obtained from this process in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of the formula H-L wherein L has the meaning defined hereinbefore. When it is desired to obtain the free base from the salt, the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the sake of convenience, in which "lower", as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention. A carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy- lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups
(for example trimethylsilylethyl); and (2-6C)alkenyl groups (for example allyl). Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed cleavage.
Examples of hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for example trimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups.
Examples of amino protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example methylidene) and benzylidene and substituted benzylidene groups.
Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as 2-nitrobenzyloxycarbonyl. The reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents and to Protective Groups in Organic Synthesis, 2nd Edition, by T. Green et al, also published by John Wiley & Son, for general guidance on protecting groups.
Quinoline starting materials of the Formula II may be obtained by conventional procedures such as those disclosed in International Patent Applications WO 98/43960 and WO 00/68201. For example, a l,4-dihydroquinolin-4-one of Formula IV
Figure imgf000049_0001
wherein m and R1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed by conventional means. The 4-chloroquinoline so obtained may be converted, if required, into a 4-pentafluorophenoxyquinoline by reaction with pentafluorophenol in the presence of a suitable base such as potassium carbonate and in the presence of a suitable solvent such as N,N-dimethylformamide. 4-Aminobenzofuran starting materials (Formula HJ, for example when Z is NH) may be obtained by conventional procedures as illustrated in the Examples. Corresponding 4-hydroxybenzofuran and 4-mercaptobenzofuran starting materials (Formula HI, when Z is O or S respectively) may be obtained by conventional procedures, (b) For the production of those compounds of the Formula I wherein at least one R1 group is a group of the formula
Figure imgf000049_0002
wherein Q1 is an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl- (l-6C)alkyl, heteroaryl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group or an optionally substituted alkyl group and X1 is an oxygen atom, the coupling, conveniently in the presence of a suitable dehydrating agent, of a quinoline of the Formula V
Figure imgf000049_0003
wherein m, R1, Z, n and R3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an appropriate alcohol wherein any functional group is protected if necessary whereafter any protecting group that is present is removed by conventional means.
A suitable dehydrating agent is, for example, a carbodiimide reagent such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of an azo compound such as diethyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
(c) For the production of those compounds of the Formula I wherein an R1 group contains a (l-6C)alkoxy or substituted (l-6C)alkoxy group or a (l-6C)alkylamino or substituted
(l-6C)alkylamino group, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of a quinoline derivative of the Formula VI
Figure imgf000050_0001
wherein L is a displaceable group as defined hereinbefore and Z, n and R3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an alcohol or amine as appropriate.
The reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 50°C. (d) For the production of those compounds of the Formula I wherein R1 is an amino-substituted (l-6C)alkoxy group (such as 2-homopiperidin-l -ylethoxy or 3-dimethylaminopropoxy), the reaction of a compound of the Formula I wherein R1 is a halogeno-substituted (l-6C)alkoxy group with a heterocyclyl compound or an appropriate amine.
The reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
(e) For the production of those compounds of the Formula I wherein R1 is a hydroxy group, the cleavage of a quinoline derivative of the Formula I wherein R1 is a (l-6C)alkoxy or arylmethoxy group. The cleavage reaction may conveniently be carried out by any of the many procedures known for such a transformation. The cleavage reaction of a compound of the Formula I wherein R1 is a (l-6C)alkoxy group may be carried out, for example, by treatment of the quinoline derivative with an alkali metal (l-6C)alkylsulphide such as sodium ethanethiolate or, for example, by treatment with an alkali metal diarylphosphide such as lithium diphenylphosphide. Alternatively the cleavage reaction may conveniently be carried out, for example, by treatment of the quinoline derivative with a boron or aluminium trihalide such as boron tribromide. The cleavage reaction of a compound of the Formula I wherein R1 is a arylmethoxy group may be carried out, for example, by hydrogenation of the quinoline derivative in the presence of a suitable metallic catalyst such as palladium or by reaction with an organic or inorganic acid, for example trifluoroacetic acid. Such reactions are preferably carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
(f) For the production of those compounds of the Formula I wherein an R1 group contains a primary or secondary amino group, the cleavage of the corresponding compound of the
Formula I wherein the R1 group contains a protected primary or secondary amino group.
Suitable protecting groups for an amino group are, for example, any of the protecting groups disclosed hereinbefore for an amino group. Suitable methods for the cleavage of such amino protecting groups are also disclosed hereinbefore. In particular, a suitable protecting group is a lower alkoxycarbonyl group such as a tert-butoxycarbonyl group which may be cleaved under conventional reaction conditions such as under acid-catalysed hydrolysis, for example in the presence of trifluoroacetic acid.
(g) For the production of those compounds of the Formula I wherein an R1 group contains a (l-6C)alkoxy or substituted (l-6C)alkoxy group or a (l-6C)alkylamino or substituted (l-6C)alkylamino group, the alkylation, conveniently in the presence of a suitable base as defined hereinbefore, of a quinoline derivative of the formula I wherein the R group contains a hydroxy group or a primary or secondary amino group as appropriate. A suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy to alkoxy or substituted alkoxy, or for the alkylation of amino to alkylamino or substituted alkylamino, for example an alkyl or substituted alkyl halide, for example a (l-6C)alkyl chloride, bromide or iodide or a substituted (l-6C)alkyl chloride, bromide or iodide, conveniently in the presence of a suitable base as defined hereinbefore, in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 140°C, conveniently at or near ambient temperature.
Conveniently for the production of those compounds of the Formula I wherein R1 contains a (l-6C)alkylamino or substituted (l-6C)alkylamino group, a reductive amination reaction may be employed. For example, for the production of those compounds of the Formula I wherein R1 contains a N-methyl group, the corresponding compound containing a N-H group may be reacted with formaldehyde in the presence of a suitable reducing agent. A suitable reducing agent is, for example, a hydride reducing agent, for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride. The reaction is conveniently performed in a suitable inert solvent or diluent, for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride. The reaction is performed at a temperature in the range, for example, 10 to 80°C, conveniently at or near ambient temperature, (h) For the production of those compounds of the Formula I wherein R1 is an amino-hydroxy-disubstituted (l-6C)alkoxy group (such as 2-hydroxy-3-pyrrolidin- 1-ylpropoxy or 3-[N-allyl-N-methylamino]-2-hydroxypropoxy), the reaction of a compound of the Formula I wherein the R1 group contains an epoxy-substituted (l-6C)alkoxy group with a heterocyclyl compound or an appropriate amine.
The reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
(i) For the production of those compounds of the Formula I wherein an R1 group contains a hydroxy group, the cleavage of the corresponding compound of the Formula I wherein the R1 group contains a protected hydroxy group.
Suitable protecting groups for a hydroxy group are, for example, any of the protecting groups disclosed hereinbefore. Suitable methods for the cleavage of such hydroxy protecting groups are also disclosed hereinbefore. In particular, a suitable protecting group is a lower alkanoyl group such as an acetyl group which may be cleaved under conventional reaction conditions such as under base-catalysed conditions, for example in the presence of ammonia, (j) For the production of those compounds of the Formula I wherein Z is a SO or SO2 group, the oxidation of a compound of Formula I wherein Z is a S group.
Conventional oxidation reagents and reaction conditions for such partial or complete oxidation of a sulphur atom are well known to the organic chemist. (k) The conversion of a compound of the Formula I wherein an R1 or R3 substituent is a halogeno group into a further compound of the Formula I wherein the R1 or R3 substituent is, for example, a cyano, ethynyl or phenyl group.
For example, a compound of the Formula I wherein an R1 or R3 substituent is a halogeno group may be reacted with a metal cyanide to form a compound of the Formula I wherein an R1 or R3 substituent is a cyano group. Conveniently, the reaction may be carried out in the presence of a suitable catalyst. A suitable metal cyanide is, for example, a heavy metal cyanide such as zinc cyanide. A suitable catalyst is, for example, an organometallic reagent, for example an organoiron compound such as diphenylphosphinoferrocene. The conversion reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 100°C.
For example, a compound of the Formula I wherein an R1 or R3 substituent is a halogeno group may be reacted with a (2-6C)alkyne to form a compound of the Formula I wherein an R1 or R3 substituent is a (2-6C)alkynyl group such as an ethynyl group. The reaction may conveniently be carried out in the presence of a suitable base as defined hereinbefore and in the presence of a suitable catalyst. For this conversion, a suitable catalyst is, for example, an organometallic reagent, for example an organopalladium compound such as tetrakis(triphenylphosphine)palladium(0). The conversion reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 60°C.
For example, a compound of the Formula I wherein an R1 or R3 substituent is a halogeno group may be reacted with an arylboron reagent to form a compound of the
1 * Formula I wherein an R or R substituent is an aryl group such as a phenyl group. A suitable arylboron reagent is, for example, an arylboronic acid. The reaction may conveniently be carried out in the presence of a suitable catalyst, for example, an organopalladium compound such as tetrakis(triphenylphosphine)palladium(0). The conversion reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 80°C.
When a pharmaceutically-acceptable salt of a quinoline derivative of the Formula I is required, for example an acid-addition salt, for use according to the invention it may be obtained by, for example, reaction of said quinoline derivative with a suitable acid using a conventional procedure. Biological Assays
The following assays can be used to measure the effects of the compounds as inhibitors of the MAPK pathway. Assay to detect MEK inhibition
To evaluate inhibitors of the MAPK pathway a coupled assay was carried out which measures phosphorylation of serine/threonine residues present in the substrate in the presence or absence of inhibitor. Recombinant glutathione S-transferase fusion protein containing human p45MEKl (GST-MEK) was activated by c-raf (Sf9 insect cell lysate from triple baculoviral infection with c-raf/ras/lck) and used for the assay. Active GST-MEK was first used to activate a recombinant glutathione S-transferase fusion protein containing p44MAP kinase (GST-MAPK) in the presence of ATP and Mg2+ for 60min at room temperature in the presence or absence of potential inhibitors. The activated GST-MAPK was then incubated with myelin basic protein (MBP) as substrate for lOmin at room temperature in the presence of ATP, Mg2+ and 33P-ATP. The reaction was stopped by addition of 20% v/v phosphoric acid. Incorporation of 33P into the myelin basic protein was determined by capture of the substrate on a filter mat, washing and counting using scintillation methods. The extent of inhibition was determined by comparison with untreated controls. The final assay solution contained lOmM Tris, pH 7.5, 0.05mM EGTA, 8.33μM
[γ33P]ATP, 8.33mM Mg(OAc)2, 0.5mM sodium orthovanadate, 0.05%w/v BSA, 6.5ng GST-MEK, lμg GST-MAPK and 16.5μg MBP in a reaction volume of 60μl. Compounds tested had IC50 results typically less than 0.5μM. In vitro MAP kinase assay
To determine whether compounds were inhibiting GST-MEK or GST-MAPK, a direct assay of MAPK activity was employed. GST-MAPK was activated by a constitutively active GST-MEK fusion protein containing two point mutations (S217E, S221E) and used for the assay in the presence and absence of potential inhibitors. The activated GST-MAPK was incubated with substrate (MBP) for 60min at room temperature in the presence of ATP, Mg2+ and 33P-ATP. The reaction was stopped by addition of 20% v/v phosphoric acid. Incorporation of 33P into the myelin basic protein was determined by capture of the substrate on a filter mat, washing and counting using scintillation methods.
The final assay solution contained 12mM Tris, pH 7.5, 0.06mM EGTA, 30μM [γ33P]ATP, lOmM Mg(OAc)2, 0.6mM sodium orthovanadate, 0.06%w/v BSA, 28ng GST-MAPK and 16.5μg MBP in a reaction volume of 60μl.
Compounds of Formula I showed activity in this screen. Cell proliferation assays Cells were seeded into multi-well plates at 20000 - 40 000 cells/ml in growth medium containing 5% FCS and incubated overnight at 37°C. The compounds were prepared in fresh medium at an appropriate concentration and added to the wells containing the cells. These were then incubated for a further 72 hours. Cells were then either removed from the wells by incubating with trypsin/EDTA and counted using a Coulter counter, or treated with XTT PMS in PBS A and optical densities read at 450nm. Compounds of Formula I had IC50 results typically less than 30/xM.
A pharmaceutical composition for the use of compounds of Formula I according to the invention comprises a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier. Thus according to a further aspect of the invention there is provided a pharmaceutical compositon which comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier for use as an anti- proliferative agent in the containment and/or treatment of solid tumour disease.
The compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
In using a compound of the Formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration is however preferred, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
The anti-proliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents :-
(i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 -reductase such as finasteride;
(iii) Agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro- 4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent
Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin); (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and WO02/08213;
(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapy approaches, including for example ex- vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of the Formula I within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range. According to this aspect of the invention there is provided the use of a pharmaceutical product comprising a quinoline derivative of the Formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the use in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
Although the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of MEK enzyme. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
The invention will now be illustrated in the following Examples in which, generally :
(i) operations were carried out at ambient temperature, i.e. in the range 17 to 25°C and under an atmosphere of an inert gas such as argon unless otherwise stated;
(ii) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration;
(iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany or high pressure liquid chromatography (HPLC) was performed on C18 reverse phase silica, for example on a Dynamax C-18 60A preparative reversed-phase column;
(iv) yields, where present, are not necessarily the maximum attainable;
(v) in general, the end-products of the Formula I have satisfactory microanalyses and their structures were confirmed by nuclear magnetic resonance (NMR) and/or mass spectral techniques; fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer and, where appropriate, either positive ion data or negative ion data were collected; NMR chemical shift values were measured on the delta scale [proton magnetic resonance spectra were determined using a Jeol JNM EX 400 spectrometer operating at a field strength of 400MHz, Varian Gemini 2000 spectrometer operating at a field strength of 300MHz or a Bruker AM300 spectrometer operating at a field strength of 300MHz]; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad;
(vi) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMR analysis;
(vii) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the Formula I were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture;
(viii) where certain compounds were obtained as an acid-addition salt, for example a mono hydrochloride salt or a dihydrochloride salt, the stoichiometry of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the salt was generally not determined, for example by means of a elemental analysis data; (ix) the following abbreviations have been used:-
DMF N,N-dimethylformamide
DMSO dimethylsulphoxide THF tetrahydrofuran
The compound in the Example below was found to be active in the assays described above. Example 1
4-benzofuran-4-yIamino-3-cyano-6-methoxy-7-[3-(4-methylpiperazin- l-yl)propoxy]quinoline dihydrochloride salt Sodium hexamethyldisilazane (1M solution in THF; 0.9 ml) was added to a solution of
4-aminobenzofuran (0.12 g) in DMF (10 ml) that had been cooled to 0°C and the mixture was stirred for 5 minutes. A solution of 4-chloro-3-cyano-6-methoxy-7-[3-(4-methylpiperazin- l-yl)propoxy] quinoline (0.17 g) in DMF (2 ml) was added and the resultant mixture was stirred at ambient temperature for 24 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. The material so obtained was dissolved in diethyl ether and a solution of hydrogen chloride in diethyl ether (1M, 2 ml) was added. The resultant solid was washed with diethyl ether and dried. There was thus obtained the title compound (0.105 g); NMR Spectrum: (DMSOd6 and CD3CO2D) 2.32 (m, 2H), 2.85 (s, 3H), 3.27-3.85 (m, lOH), 4.0 (s, 3H), 4.33 (m, 2H), 7.07 (d, 1H), 7.35 (t, 1H), 7.43 (d, 1H), 7.51 (s, 1H), 7.72 (d, 1H), 7.96 (d, 1H), 8.22 (s, 1H), 8.92 (s, 1H); Mass Spectrum : M+ϊ 472. The 4-aminobenzofuran used as a starting material was prepared as follows :-
Allyl bromide (12.5 ml) and sodium iodide (1 g) were added in turn to a stirred mixture of methyl 3-hydroxybenzoate (20 g), potassium carbonate (22 g) and acetone (200 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was filtered and the solvent was evaporated. The residue was partitioned between methylene chloride and water. The organic phase was dried over magnesium sulphate and evaporated and the residue was purified by column chromatography using increasingly polar mixtures of petroleum ether (b.p. 60-80°C) and ethyl acetate as eluent. There was thus obtained methyl 3-allyloxybenzoate as an oil (21.8 g); NMR Spectrum: (DMSOdδ) 3.85 (s, 3H), 4.65 (d, 2H), 5.30 (m, 1H), 5.45 (m, 1H), 6.05 (m, 1H), 7.25 (m, 1H), 7.45 (m, 2H), 7.55 (d, 1H).
The methyl 3-allyloxybenzoate so obtained was heated to 200°C for 0.7 hours and then to 230°C for 1 hour. The reaction product, comprising a mixture of methyl 2-allyl- 3-hydroxybenzoate and methyl 4-allyl-3-hydroxybenzoate, was cooled to ambient temperature and partitioned between diethyl ether and IN aqueous potassium hydroxide solution. The aqueous phase was allowed to stand for 30 minutes whereupon the methyl 4-allyl- 3-hydroxybenzoate was hydrolysed to 4-allyl-3-hydroxybenzoic acid. The aqueous phase was then acidified to pHl by the addition of 6N aqueous hydrochloric acid and extracted with diethyl ether. The organic extract was washed with 10% aqueous potassium carbonate solution, dried over magnesium sulphate and evaporated. There was thus obtained methyl 2-allyl-3-hydroxybenzoate (10.7 g) as an oil; Mass Spectrum: M+H 192.
Using analogous procedures to those described in J. Med. Chem., 1995, 38, 3102- 3103, methyl 2-allyl-3-hydroxybenzoate was converted in three steps via methyl 2-hydroxy- 2,3-dihydrobenzofuran-4-carboxylate and methyl benzofuran-4-carboxylate into benzofuran- 4-carboxylic acid.
A mixture of benzofuran-4-carboxylic acid (0.5 g), diphenylphosphoryl azide (1.2 ml), triethylamine (0.79 ml) and tert-butanol (1.5 ml) were stirred and heated to reflux for 18 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography using methylene chloride as eluent. There was thus obtained tert-butyl benzofuran-4- carbamate (0.8 g) as an oil; Mass Spectrum: M+Na+ 256.
Trifluoroacetic acid (2.5 ml) was added to a solution of tert-butyl benzofuran- 4-carbamate (0.65 g) and methylene chloride (20 ml) which had been cooled to 0°C and the mixture was stirred for lhour. The mixture was allowed to warm to ambient temperature and stirring was continued for 1.5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulphate and evaporated. The resultant oil was purified by column chromatography using a 4: 1 mixture of methylene chloride and petroleum ether (b.p. 60-80°C) as eluent. There was thus obtained 4-aminobenzofuran (0.35 g); NMR Spectrum: (DMSOde) 5.5 (br s, 2H), 6.35 (d, 1H), 6.7 (d, 1H), 6.95 (d, 1H), 7.0 (d, 1H), 7.7 (d, 1H); Mass Spectrum: M+H+ 133.
The 4-chloro-3-cyano-6-methoxy-7-[3-(4-methylpiperazin- 1 -yl)propoxy]quinoline used as a starting material was prepared as follows :-
A mixture of 3-bromopropanol (20 ml), N-methylpiperazine (29 ml), potassium carbonate (83 g) and ethanol (200 ml) was stirred and heated to reflux for 20 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was triturated under diethyl ether. The resultant mixture was filtered and the filtrate was evaporated. The residue was purified by distillation at about 60-70°C under about
0.2 mm Hg to give l-(3-hydroxypropyl)-4-methylpiperazine (17 g); NMR Spectrum: (CDC13) 1.72 (m, 2H), 2.3 (s, 3H), 2.2-2.8 (m, 8H), 2.6 (t, 2H), 3.8 (t, 2H), 5.3 (br s, 1H). Diethyl azodicarboxylate (0.25 g) was added dropwise to a suspension of 4-chloro- 3-cyano-7-hydroxy-6-methoxyquinoline (0.2 g; , prepared as described in International Patent Application WO 00/68201, disclosed as compound (7) within Preparation 1 therein), l-(3-hydroxypropyl)-4-methylpiperazine (0.202 g), triphenyl phosphine (0.447 g) and methylene chloride (5 ml) and the mixture was stirred at ambient temperature for 2 hours. The resultant mixture was evaporated and the residue was purified by column chromatography on silica using initially increasingly polar mixtures of methylene chloride and ethyl acetate followed by increasingly polar mixtures of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was isolated and dried under vacuum to give the required starting material (0.15 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.95-2.05 (m, 2H), 2.2 (s, 3H), 2.25-2.5 (m, 10H), 4.05 (s, 3H), 4.3 (m, 2H), 7.45 (s, 1H), 7.58 (s, 1H), 9.0 (s, 1H); Mass Spectrum: M+H* 375 and 377. Example 2 Pharmaceutical composition
The following illustrates a representative pharmaceutical dosage form of the invention as defined herein (the active ingredient being termed "Compound X"), for therapeutic or prophylactic use in humans:
Tablet I mg/tablet
Compound X 100 Lactose Ph.Eur 182.75
Croscarmellose sodium 12.0
Maize starch paste (5% w/v paste) 2.25
Magnesium stearate 3.0
The above formulation may be obtained by conventional procedures well known in the pharmaceutical art. The tablet may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

Claims

The use of a quinoline derivative of the Formula I
Figure imgf000064_0001
wherein Z is an O, S, SO, SO2, N(R2) or C(R2)2 group, wherein each R2 group, which may be the same or different, is hydrogen or (l-6C)alkyl; m is O, 1, 2, 3 or 4; each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulρhinyl, (l-6C)alkylsulphonyl,
(l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl] carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl- (3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
Q'-X1 - wherein X1 is a direct bond or is selected from O, S, SO, SO2, N(R4), CO, CH(OR4), CON(R4), N(R4)CO, SO2N(R4), N(R4)SO2, OC(R4)2, SC(R4)2 and N(R4)C(R4)2, wherein R4 is hydrogen or (l-6C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or (R^m is (l-3C)alkylenedioxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)CO, SO2N(R5), N(R5)SO2, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl or, when the inserted group is N(R5), R5 may also be
(2-6C)alkanoyl, and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyl]amino-(l-6C)alkyl or from a group of the formula :
Q2-X2- wherein X2 is a direct bond or is selected from CO and N(R6)CO, wherein R6 is hydrogen or (l-6C)alkyl, and Q2 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl- (2-6C)alkanoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
-X3-Q3 wherein X3 is a direct bond or is selected from O, S, SO, SO2, N(R7), CO, CH(OR7), CON(R7), N(R7)CO, SO2N(R7), N(R7)SO2, C(R7)2O, C(R7)2S and N(R7)C(R7)2, wherein R7 is hydrogen or (l-6C)alkyl, and Q3 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulρhinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(l-6C)alkyl-(2-6C)alkanoylamino, N-(l-6C)alkylsulρhamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl- (l-6C)alkanesulphonylamino, or from a group of the formula : -X -R8 wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino- (l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, or from a group of the formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents; n is O, 1, 2 or 3; and R3 is halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-
(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
-X6-Rπ wherein X6 is a direct bond or is selected from O and N(R12), wherein R12 is hydrogen or (l-6C)alkyl, and R11 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl or di-[(l-6C)alkyl]amino-(l-6C)alkyl, or from a group of the formula : -X7-Q5 wherein X7 is a direct bond or is selected from O, S, SO, SO2, N(R13), CO, CH(OR13), CON(R13), N(R13)CO, SO2N(R13), N(R13)SO2, C(R13)2O, C(R13)2S and N(R13)C(R13)2, wherein R13 is hydrogen or (l-6C)alkyl, and Q5 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and any heterocyclyl group within Q5 optionally bears 1 or 2 oxo or thioxo substituents, or a pharmaceutically-acceptable salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
2. The use of a quinoline derivative of the Formula I as claimed in claim 1 wherein m is 1 or 2, and each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino and N-(l-6C)alkyl- (2-6C)alkanoylamino, or from a group of the formula :
Q^ -X1 - wherein X1 is selected from O, N(R4), CON(R4), N(R4)CO and OC(R4)2 wherein R4 is hydrogen or (l-6C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or X1 is a direct bond and Q1 is aryl-(l-6C)alkyl, cycloalkyl-(l-6C)alkyl, heteroaryl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R5), CON(R5), N(R5)CO, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl, or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno groups or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (2-6C)alkanoyloxy, (2-6C)alkanoylamino and N-(l-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula : -X3-Q3 wherein X3 is a direct bond or is selected from O, N(R6), CON(R7), N(R7)CO and C(R7)2O,
7 ^ wherein R is hydrogen or (l-6C)alkyl, and Q is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsulphonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoyl, or optionally bears 1 substituent selected from a group of the formula :
-X4-R8 wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, and from a group of the formula :
-X5-Q4 wherein X is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents, in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
3. The use of a quinoline derivative of the Formula I as claimed in claim 1 wherein R1 substituents may only be located at the 5-, 6- and/or 7-positions on the quinoline ring, in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
4. The use of a quinoline of Formula I wherein: Z is O or NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy,
3-(N-isopropyl-N-methylamino)proρoxy, 4-(N-isopropyl-N-methylamino)butoxy, 2-(N-isobutyl-N-methylamino)ethoxy, 3-(N-isobutyl-N-methylamino)propoxy, 4-(N-isobutyl-N-methylamino)butoxy, 2-(N-allyl-N-methylamino)ethoxy, 3-(N-allyl-N-methylamino)propoxy, 2-(N-prop-2-ynylamino)ethoxy, 3-(N-prop-2-ynylamino)propoxy, 2-(N-methyl-N-prop-2-ynylamino)ethoxy, 3-(N-methyl-N-prop-2-ynylamino)propoxy, 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3 -yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethoxy, 3-(l,l-dioxotetrahydro-
4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, N-cyanomethylpiperidin-3 -ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, N-cyanomethylpiperidin-4-ylmethoxy,
2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy, 2-homopiperidin-l -ylethoxy, 3-homopiperidin-l-ylpropoxy, 4-homopiperidin-l -ylbutoxy, 2-piperazin-l -ylethoxy, 2-(4-methylpiperazin- l-yl)ethoxy, 3-piperazin- 1 -ylpropoxy, 3-(4-methylpiperazin- 1 -yl)propoxy , 4-piperazin- 1 -ylbutoxy, 4-(4-methylpiperazin- 1 -yl)butoxy, 2-(4-allylρiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 4-(4-allylpiperazin-l-yl)butoxy, 2-(4-methylsulphonylpiperazin-l-yl)ethoxy, 3-(4-methylsulphonylpiperazin-l-yl)propoxy, 4-(4-methylsulphonylpiperazin- 1 -yl)butoxy, 2-(4-acetylpiperazin- 1 -yl)ethoxy , 3-(4-acetylpiperazin- 1 -yl)propoxy, 4-(4-acetylpiperazin- 1 -yl)butoxy, 2-(4-cyanomethylpiperazin- 1 -yl)ethoxy, 3-(4-cyanomethylpiperazin- 1 -yl)propoxy, 4-(4-cyanomethylpiperazin- 1 -yl)butoxy, 2-(2-piperazin- 1 -ylethoxy)ethoxy ,
2- [2-(4-methylpiperazin- 1 -yl)ethoxy] ethoxy, 2-chloroethoxy , 3-chloropropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-tetrahydropyran-4-ylethoxy, 3-tetrahydropyran-4-ylpropoxy, 2-pyrrol- 1 -ylethoxy, 3 -pyrrol- 1 -ylpropoxy, 2-(2-ρyridyloxy)ethoxy, 3-(2-pyridyloxy)propoxy, 2-(3-pyridyloxy)ethoxy, 3-(3-pyridyloxy)propoxy, 2-(4-pyridyloxy)ethoxy, 3-(4-pyridyloxy)propoxy, 2-pyridylmethoxy, 3-pyridylmethoxy and 4-pyridylmethoxy, and wherein any CH2 group within the second R1 group that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heteroaryl group within the second R1 group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl, and any heterocyclyl group within the second R1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R group, if present, is located at the 6-position of the benzofuran-4-yl group and is selected from fluoro, chloro and bromo, or a pharmaceutically-acceptable acid-addition salt thereof; in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
5. The use of a quinoline derivative of the Formula I as claimed in claim 1 wherein : m is 2 and the first R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, N-methylpyrrolidin-3-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second R1 is located at the 7-position and is selected from methoxy, benzyloxy, 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-piperidinoethoxy,
3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(4-methylpiperazin- l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy and 3-methylsulphonylpropoxy; n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuran-4-yl group and is selected from chloro and bromo; or a pharmaceutically-acceptable acid-addition salt thereof, in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
6. The use of a quinoline derivative of the Formula I as claimed in claim 1 wherein : Z is NH; m is 1 and the R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, and the second R1 group is located at the 7-position and is selected from methoxy, ethoxy, propoxy, 3-pyrrolidin-l-ylpropoxy, 3-piperidinopropoxy, 3-morpholinopropoxy, 3-piperazin-l-ylpropoxy and 3-(4-methylpiperazin-l-yl)propoxy; n is 0 or n is 1 and the R3 group, if present, is a chloro group located at the 5-position of the benzofuran-4-yl group; or a pharmaceutically-acceptable acid-addition salt thereof, in the manufacture of a medicament for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
7. A method for producing an anti-proliferative effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6.
8. The use of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use in the prevention or treatment of tumours which are sensitive to inhibition of MEK enzymes that are involved in the MAPK pathway.
9. A method for the prevention or treatment of tumours which are sensitive to inhibition of MEK enzymes that are involved in the MAPK pathway which comprises administering to a warm-blooded animal in need of treatment an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6.
10. A pharmaceutical composition which comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6 in association with a pharmaceutically acceptable diluent or carrier for use as an anti-proliferative agent in the containment and/or treatment of solid tumour disease.
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US10865214B2 (en) 2015-10-05 2020-12-15 The Trustees of Columbia University in they City of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11008341B2 (en) 2015-10-05 2021-05-18 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11230558B2 (en) 2015-10-05 2022-01-25 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11261199B2 (en) 2015-10-05 2022-03-01 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies

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